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CLINICAL
Immunology
PRINCIPLES AND PRACTICE
 CLINICAL
Immunology PRINCIPLES AND PRACTICE
SIXTH EDITION

Robert R. Rich, MD
Dean and Professor Emeritus
Medicine
University of Alabama at Birmingham;
Former Senior Vice President for Medicine
School of Medicine
University of Alabama at Birmingham
Birmingham, AL, United States

Thomas A. Fleisher, MD Cornelia M. Weyand, MD, PhD

Executive Vice President Professor Emerita
American Academy of Allergy, Asthma, and Immunology Medicine
Milwaukee, WI, United States; Stanford University
Scientist Emeritus Stanford, CA, United States;
National Institutes of Health Clinical Center Professor
Bethesda, MD, United States Medicine and Immunology
Mayo Clinic Alix School of Medicine
Harry W. Schroeder Jr., MD, PhD Rochester, MN, United States
Professor
Medicine, Microbiology, and Genetics David B.Corry, MD
University of Alabama at Birmingham Professor
Birmingham, AL, United States Medicine and Pathology and Immunology
Baylor College of Medicine
Houston, TX, United States

Jennifer M. Puck, MD
Professor of Pediatrics
University of California San Francisco
San Francisco, CA, United States
© 2023, Elsevier Ltd. All rights reserved.
First edition 1996
Second edition 2001
Third edition 2008
Fourth edition 2013
Fifth edition 2019
Sixth edition 2023

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This book and the individual contributions contained in it are protected under copyright by the Publisher
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Chapter 14, Cytokines and cytokine receptors; John J. O’Shea and Massimo Gadina︎ contributions are in the
public domain.
Chapter 15: Chemokines and Chemokine Receptors; Philip Murphy contributions are in the public domain
Chapter 28: Host Defenses to Fungi; Michail S. Lionakis︎ contributions are in the public domain
Chapter 45: Eosinophils and Eosinophilic Disorders; Amy D. Klion︎ contributions are in public domain
Chapter 78, Lymphomas; Elaine S. Jaffe and Stefania Pittaluga contributions are in the public domain.
Chapter 85, Protein kinase antagonists; John J. O’Shea and Massimo Gadina contributions are in the public
domain.
Chapter 90: Allogeneic Transplantation for Immunodeficiency is in the public domain
Chapter 93: Flow cytometry; Sergio Rosenzweig contributions are in the public domain.

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 CONTENTS

Preface to the First Edition, ix PART III H

Preface to the Sixth Edition, xi
List of Contributors, xiii
Dedication, xxvii
PART I Principles of Immune Response
1 The Human Immune Response, 2
Robert R. Rich and Randy Q. Cron
2 Organization of the Immune System, 17
Dorothy E. Lewis, Arthur W. Zieske, and Sarah E. Blutt
3 Innate Immunity, 39
Douglas R. McDonald and Ofer Levy
4 Antigen Receptor Genes, Gene Products, and
Co-Receptors, 55
Harry W. Schroeder Jr., Laurent Gapin, and Raul Martin Torres
5 The Major Histocompatibility Complex, 78
Dimitri S. Monos and Raja Rajalingam
6 Antigens and Antigen Presentation, 93
Harry W. Schroeder Jr. and Robert R. Rich
7 B-Cell Development and Differentiation, 107
Harry W. Schroeder Jr., Andreas Radbruch, and Claudia Berek
8 Immunoglobulin Function, 120
Neil S. Greenspan
9 T-Cell Development, 130
S. Thera Lee and Kristin Hogquist
10 T-Cell Activation and Tolerance, 137
Erik J. Peterson
11 Helper T-Cell Subsets and Control of the Inflammatory
Response, 151
Todd N. Eagar and Stephen D. Miller
12 Cytotoxic T Lymphocytes and Natural Killer Cells, 162
Stephen L. Nutt and Nicholas D. Huntington
13 Regulatory Immune Cells, 175
James B. Wing and Shimon Sakaguchi
14 Cytokines and Cytokine Receptors, 186
John J. O’Shea, Massimo Gadina, Giuseppe Sciumè, and Françoise Meylan
15 Chemokines and Chemokine Receptors, 215
Philip M. Murphy
16 Lymphocyte Adhesion and Trafficking, 228
Sirpa Jalkanen and Marko Salmi
17 Death Pathways and Immunogenicity, 239
Wulf Tonnus, Alexia Belavgeni, and Andreas Linkermann
PART II F undamentals of Host-Environmental
Interactions
18 Human Genomics in Immunology, 249
Jennifer M. Puck and Robert L. Nussbaum
19 Regulatory RNA in Immunologic Diseases, 258
Thomas M. Aune
20 Immunometabolism, 265
Michihito Kono, Amir Sharabi, and George C. Tsokos
21 Immune Deficiencies at the Extremes of Age, 272
Claire E. Gustafson, Cornelia M. Weyand, and Jörg J. Goronzy
22 The Microbiota in Immunity and Inflammation, 281
Craig L. Maynard
 ost Defenses to Infectious
Agents
23 Immunology of the Skin, 295
Hui Xu, Nabiha Yusuf, and Craig A. Elmets
24 Immunology of Mucosal Surfaces, 306
Prosper N. Boyaka and Kohtaro Fujihashi
25 Host Defenses to Viruses, 320
Scott N. Mueller and Barry T. Rouse
26 Host Defenses to Intracellular Bacteria, 331
Stephen T. Reece and Stefan H. E. Kaufmann
27 Host Defenses to Extracellular Bacteria, Including
Spirochetes, 347
Sarah W. Satola, Marcos C. Schechter, Shyra Wilde, and David S.
Stephens
28 Host Defenses to Fungi, 361
Tobias M. Hohl, Bruce S. Klein, and Michail S. Lionakis
29 Host Defenses to Protozoa, 375
Robin Stephens, Jude E. Uzonna, and Sara M. Dann
30 Host Defenses to Helminth Infection, 386
Subash Babu and Thomas B. Nutman
31 Emerging Pandemic Infectious Disease
Threats, 399
David B. Corry, Peter J. Hotez, Maria Bottazzi, Jill Weatherhead,
Anthony Maresso, Emmaline Heckmann, and Lynn Bimler
PART IV I mmune Deficiency and Immune
Regulatory Disorders
32 Approach to the Evaluation of the Patient With Suspected
Immunodeficiency, 413
Jennifer M. Puck and Thomas A. Fleisher
33 Primary Antibody Deficiencies, 420
Tracy Hwangpo and Harry W. Schroeder Jr.
34 Primary T-Cell Immunodeficiencies, 438
Luigi D. Notarangelo
35 Genetic Disorders of Interferons-, Interleukin-17,
Interleukin-18, and Nuclear Factor-κB-Mediated
Immunity, 457
Jacinta Bustamante, Shen-Ying Zhang, Bertrand Boisson,
Vivien Béziat, Qian Zhang, Emmanuelle Jouanguy,
Stéphanie Boisson-Dupuis, Anne Puel, and Jean-Laurent Casanova
36 Hemophagocytic Lymphohistiocytosis, 469
Michael B. Jordan and Adi Zoref Lorenz
37 Autoinflammatory Syndromes, 474
Catharina M. Mulders-Manders, Jeroen C. H. van der Hilst, Jos W. M.
van der Meer, and Anna Simon
38 Immune Regulatory Disorders, 484
Troy R. Torgerson and Alice Y. Chan
39 Neutrophils and Neutrophil Disorders, 491
Steven M. Holland and Gülbü Uzel
40 Complement and Complement Disorders, 506
John P. Atkinson, M. Kathryn Liszewski, Anuja Java, and Hrishikesh S.
Kulkarni

v
vi Contents

41 Human Immunodeficiency Virus Infection and Acquired 64 Immunology of Psoriasis, 824

Immunodeficiency Syndrome, 525 Cristina Albanesi
Susan L. Gillespie, Javier Chinen, and Mary E. Paul 65 Myasthenia Gravis, 832
42 Autoantibody-Mediated Phenocopies of Primary Patricia M. Sikorski, Linda L. Kusner, and Henry J. Kaminski
Immunodeficiency Diseases, 542 66 Multiple Sclerosis, 843
Jennifer D. Treat, Sarah K. Browne, and Christa S. Zerbe Andrew R. Romeo and Benjamin M. Segal
67 Autoimmune Peripheral Neuropathies, 854
Marinos C. Dalakas
PART V Allergic Diseases 68 Immunologic Renal Diseases, 866
43 Allergic Airway Diseases, 551 Tilo Freiwald, Meryl Waldman, and Behdad Afzali
David B. Corry, Evan Li, and Amber U. Luong 69 Immunologic Mechanisms of Atherosclerosis and
44 Mast Cells and Mast Cell Disorders, 561 Myocarditis, 883
Cem Akin, Michelle Al-Hosni, and Dilawar Singh Khokar Peter Libby and Andrew H. Lichtman
45 Eosinophils and Eosinophilic Disorders, 573 70 Autoimmune Thyroid Diseases, 898
Amy D. Klion and Paneez Khoury Laura C. Lane, Simon H. S. Pearce, and Anna L. Mitchell
46 Urticaria, Angioedema, and Anaphylaxis, 586 71 Type 1 Diabetes, 909
Elena Borzova and Clive E. H. Grattan Leonard C. Harrison
47 Allergic Reactions to Stinging and Biting Insects, 601 72 Immunologic Lung Diseases, 919
Anna Gschwend and Arthur Helbling Scott M. Matson, Joyce S. Lee, and Andrew P. Fontenot
48 Atopic and Contact Dermatitis, 609 73 Chronic Obstructive Pulmonary Disease and
Mark Boguniewicz, Luz Fonacier, and Donald Y. M. Leung Emphysema, 936
49 Food Allergy, 623 Tillie-Louise Hackett, Francesca Polverino, and Farrah Kheradmand
J. Andrew Bird and A. Wesley Burks 74 Immunologic Ocular Disease, 943
50 Drug Hypersensitivity, 630 Michel M. Sun and Lynn K. Gordon
Shyam R. Joshi, Whitney Salinas, and David A. Khan 75 Immunologic Diseases of the Gastrointestinal
Tract, 959
Peter J. Mannon
PART VI Systemic Immune Diseases 76 Inflammatory Hepatobiliary Diseases, 972
Benedetta Terziroli Beretta-Piccoli, Carlo Selmi, Michael P. Manns, and
51 Mechanisms of Autoimmunity, 649 M. Eric Gershwin
Tory P. Johnson, Brendan Antiochos, and Antony Rosen
52 Systemic Lupus Erythematosus, 657
Cynthia Aranow, Betty Diamond, and Meggan Mackay PART VIII I mmunology and Immunotherapy of
53 Rheumatoid Arthritis, 678 Neoplasia
Andrew P. Cope
54 Juvenile Idiopathic Arthritis, 693 77 Lymphoid Leukemias, 984
Randy Q. Cron, Peter Weiser, and Timothy Beukelman Sarah Elitzur, Shai Izraeli, Dina Ben-Yehuda, and Moshe E. Gatt
55 Sjögren’s Syndrome, 704 78 Lymphomas, 1000
Vasiliki Koulouri, George Fragoulis, and Clio P. Mavragani Stefania Pittaluga, Ivo M. B. Francischetti, Joo Y. Song, and Elaine S.
56 Scleroderma-Systemic Sclerosis, 712 Jaffe
John Varga and Fredrick M. Wigley 79 Monoclonal Gammopathies, 1014
57 Inflammatory Muscle Diseases, 723 Angela Dispenzieri
Arash H. Lahouti and Lisa Christopher-Stine 80 Immune Responses to Solid Tumors and Immune
58 Spondyloarthritis, 734 Checkpoint Therapy, 1028
John D. Reveille and Lauren K. Ridley Satya Das, Justin M. Balko, and Douglas B. Johnson
59 Small- and Medium-Vessel Primary Vasculitis, 754 81 CAR T-Cell Therapy, 1042
Raashid Ahmed Luqmani, Tamir Malley, Ana Águeda, and Lorraine Cliona M. Rooney
O’Neill
60 Large Vessel Vasculitides, 773
Cornelia M. Weyand PART IX M
 edical Management of Immunological
61 Antiphospholipid Syndrome, 788 Diseases
Molly M. Daughety, Doruk Erkan, Michael D. Lockshin,
and Thomas L. Ortel 82 Immunoglobulin Therapy: Replacement and
Immunomodulation, 1051
Mark Ballow
PART VII O
 rgan-Specific Inflammatory 83 Glucocorticoids, 1061
Disease Anthony J. Frew † and David B. Corry
84 Immunomodulating Drugs, 1072
62 Immunohematologic Disorders, 796 Gideon P. Smith and Edwin S. L. Chan
Kristin Ammon Shimano and Pierre Noel 85 Protein Kinase Antagonists, 1080
63 Bullous Diseases of the Skin and Mucous Arian Laurence, Massimo Gadina, Pamela L. Schwartzberg, and John J.
Membranes, 806 O’Shea
Ralf J. Ludwig and Enno Schmidt
 Contents vii

86 Biologic Response Modifiers, 1089 PART XI Diagnostic Immunology

John M. Bridges and Walter Winn Chatham
87 Vaccines, 1102 93 Flow Cytometry, 1185
Katherine V. Houser, Myra Happe, Rachel Bean, and Emily E. Coates Cristiane J. Nunes-Santos, Sergio D. Rosenzweig, and Thomas A.
88 Allergen Immunotherapy for Allergic Diseases, 1117 Fleisher
Joana Cosme and Stephen R. Durham 94 Assessment of Functional Immune Responses in
Lymphocytes, 1198
Roshini Sarah Abraham
PART X Transplantation 95 Assessment of Neutrophil Function, 1214
Debra Long Priel and Douglas B. Kuhns
89 Solid Organ Transplantation: Rejection,
Immunosuppression, and Tolerance, 1128 96 Assessment of Human Allergic Diseases, 1225
Robert G. Hamilton
Elinor C. Mannon, Kathryn J. Wood, and Roslyn B. Mannon
90 Allogeneic Transplantation for Immunodeficiency, 1146
Sung-Yun Pai Appendix 1: Selected CD Molecules and Their
91 Gene Therapy for Primary Immune Deficiency Characteristics, 1235
Diseases, 1161 Thomas A. Fleisher
Caroline Y. Kuo and Donald B. Kohn Appendix 2: Laboratory Reference Values, 1241
92 Hematopoietic Stem Cell Transplantation for Malignant Thomas A. Fleisher
Diseases, 1172 Index, 1243
Pashna N. Munshi, Scott D. Rowley, and Robert Korngold
 P R E FA C E T O T H E F I R S T E D I T I O N
Clinical immunology is a discipline with a distinguished history,
rooted in the prevention and treatment of infectious diseases in
the late nineteenth and early twentieth centuries. The conquest
of historical scourges such as smallpox and (substantially) polio
and relegation of several other diseases to the category of medi-
cal curiosities is often regarded as the most important achieve-
ment of medical science of the past fifty years. Nevertheless, the
challenges facing immunologists in the efforts to control infec-
tious diseases remain formidable; HIV infection, malaria, and
tuberculosis are but three examples of diseases of global import
that elude control despite major commitments of monetary and
intellectual resources.
Although firmly grounded in the study and application
of defenses to microbial infection, since the 1960s, clinical
immunology has emerged as a far broader discipline. Dysfunc-
tion of the immune system has been increasingly recognized as
a pathogenic mechanism that can lead to an array of specific
diseases and failure of virtually every organ system. Paradoxi-
cally, although the importance of the immune system in dis-
ease pathogenesis is generally appreciated, the place of clinical
immunology as a practice discipline has been less clear. As most
of the noninfectious diseases in the human immune system
eventually lead to the failure of other organs, it has been organ-
specific subspecialists who have usually dealt with their conse-
quences. Recently, however, the outlook has begun to change as
new diagnostic tools increasingly allow the theoretical possibility
of intervention much earlier in disease processes, often before
irreversible target organ destruction occurs. More importantly,
this theoretical possibility is increasingly realized as clinical
immunologists find themselves in the vanguard of translating
molecular medicine from laboratory bench to patient bedside.
In many settings, clinical immunologists today function as
primary care physicians in the management of patients with
immune-deficiency, allergic, and autoimmune diseases. Indeed
many influential voices in the clinical disciplines of allergy and
rheumatology support the increasing coalescence of these tradi-
tional subspecialties around their intellectual core of immunol-
ogy. In addition to his or her role as a primary care physician,
the clinical immunologist is increasingly being looked to as a
consultant, as scientific and clinical advances enhance his or her
expertise. The immunologist with a “generalist” perspective can
be particularly helpful in the application of unifying principles
of diagnosis and treatment across the broad spectrum of immu-
nologic diseases.
Clinical Immunology: Principles and Practice has emerged
from this concept of the clinical immunologist as both primary
care physician and expert consultant in the management of
patients with immunologic diseases. It opens in full apprecia-
tion of the critical role of fundamental immunology in this
rapidly evolving clinical discipline. Authors of basic science
chapters were asked, however, to cast their subjects in a con-
text of clinical relevance. We believe the result is a well-balanced
exposition of basic immunology for the clinician.
The initial two sections on basic principles of immunology
are followed by two sections that focus in detail on the role of
the immune system in defenses against infectious organisms.
The approach is two-pronged. It begins first with a systematic
survey of immune responses to pathogenic agents followed by
a detailed treatment of immunologic deficiency syndromes.
Pathogenic mechanisms of both congenital and acquired
immune deficiency diseases are discussed, as are the infec-
tious complications that characterize these diseases. Befitting
its importance, the subject of HIV infection and AIDS receives
particular attention, with separate chapters on the problem of
infection in the immunocompromised host, HIV infection in
children, anti-retroviral therapy, and current progress in the
development of HIV vaccines.
The classic allergic diseases are the most common immuno-
logic diseases in the population, ranging from atopic disease to
drug allergy to organ-specific allergic disease (e.g., of the lungs,
eye, and skin). They constitute a foundation for the practice
of clinical immunology, particularly for those physicians with
a practice orientation defined by formal subspecialty training
in allergy and immunology. A major section is consequently
devoted to these diseases, with an emphasis on pathophysiology
as the basis for rational management.
The next two sections deal separately with systemic and
organ-specific immunologic diseases. The diseases considered
in the first of these sections are generally regarded as the core
practice of the clinical immunologist with a subdisciplinary
emphasis in rheumatology. The second section considers dis-
eases of specific organ failure as consequences of immuno-
logically mediated processes that may involve virtually any
organ system. These diseases include, as typical examples,
demyelinating diseases, insulin-dependent diabetes mellitus,
glomerulonephritides, and inflammatory bowel diseases. It is
in the management of such diseases that the discipline of clini-
cal immunology will have an increasing role as efforts focus on
intervention early in the pathogenic process and involve diag-
nostic and therapeutic tools of ever-increasing sophistication.
One of the major clinical areas in which the expertise of a
clinical immunologist is most frequently sought is that of allo-
geneic organ transplantation. A full section is devoted to the
issue of transplantation of solid organs, with an introductory
chapter on general principles of transplantation and manage-
ment of transplantation rejection followed by separate chapters
dealing with the special problems of transplantation of specific
organs or organ systems.
Appreciation of both the molecular and clinical features
of lymphoid malignancies is important to the clinical immu-
nologist regardless of subspecialty background, notwithstand-
ing the fact that primary responsibility for the management of
such patients will generally fall to the hematologist/oncologist.
A separate section is consequently devoted to the lymphocytic
leukemias and lymphomas that constitute the majority of malig-
nancies seen in the context of a clinical immunology practice.
The separate issues of immune responses to tumors and immu-
nological strategies to treatment of malignant diseases are
subjects of additional chapters.
Another important feature is the attention to therapy of
immunologic diseases. This theme is constant throughout the
chapters on allergic and immunologic diseases, and because of
the importance the editors attach to clinical immunology as a
therapeutic discipline, an extensive section is also devoted specifi-
cally to this subject. Subsections are devoted to issues of immu-
nologic reconstitution, with three chapters on the treatment of
ix
x Preface To The First Edition
immunodeficiencies, malignancies, and metabolic diseases
by bone marrow transplantation. Also included is a series of
chapters on pharmaceutical agents currently available to clini-
cal immunologists, both as anti-allergic and anti-inflammatory
drugs, as well as newer agents with greater specificity for
T cell-mediated immune responses. The section concludes with
a series of chapters that address established and potential appli-
cations of therapeutic agents and approaches that are largely
based on the new techniques of molecular medicine. In addition
to pharmaceutical agents, the section deals in detail with such
subjects as apheresis, cytokines, monoclonal antibodies and
immunotoxins, gene therapy, and new experimental approaches
to the treatment of autoimmunity. The book concludes with a
section devoted to approaches and specific techniques involved
in the diagnosis of immunologic diseases. The use of the diag-
nostic laboratory in the evaluation of complex problems of
immunopathogenesis has been a hallmark of the clinical immu-
nologist since the inception of the discipline, and many clini-
cal immunologists serve as directors of diagnostic immunology
laboratories. Critical assessment of the utilization of techniques
ranging from lymphocyte cloning to flow cytometric phenotyp-
ing to molecular diagnostics is certain to continue as an impor-
tant function of the clinical immunologist, particularly in his or
her role as an expert consultant.
In summary, we have intended to provide the reader with a
comprehensive and authoritative treatise on the broad subject
of clinical immunology, with particular emphasis on the diag-
nosis and treatment of immunological diseases. It is anticipated
that the book will be used most frequently by the physician
specialist practicing clinical immunology, both in his or her
role as a primary physician and as a subsequent consultant. It
is hoped, however, that the book will also be of considerable
utility to the non-immunologist. Many of the diseases discussed
authoritatively in the book are diseases commonly encountered
by the generalist physician. Indeed, as noted, because clinical
immunology involves diseases of virtually all organ systems,
competence in the diagnosis and management of immunologi-
cal diseases is important to virtually all clinicians. The editors
would be particularly pleased to see the book among the refer-
ences readily available to the practicing internist, pediatrician,
and family physician.
Robert R. Rich
Thomas A. Fleisher
Benjamin D. Schwartz
William T. Shearer
Warren Strober
1996
 P R E FA C E T O T H E S I X T H E D I T I O N
At the time this preface was prepared, our world was being
arguably faced with its worst infectious pandemic since the
global influenza A infection of the early 20th century. That pan-
demic infected ~500 million people, or ~1/3 of the total world
population, and caused at least 50 million deaths. The current
21st century COVID-19 pandemic was estimated in September
2021 to have infected >230 million individuals out of 7.7 billion
(~3%), causing ~4.71 million deaths; and these numbers are
also staggering and are necessarily incomplete. But as we learn
more about the prevention, diagnosis, and care of persons with
COVID-19 infections (both symptomatic and asymptomatic),
we have reason to believe that despite the enormous case load,
we will not approach the death rate of the 1918–20 pandemic.
This improved survival reflects in part the knowledge that
has been gained over the past century from research in immu-
nology, which has been contributed by investigators and clini-
cians throughout the world. This knowledge has advanced our
ability to prevent and manage pandemics in general, giving
us hope to face future emerging infectious disease challenges
as well.
Although clinical immunology and this book are strongly
grounded in the study of and application to microbial infections,
both the book and the discipline are far broader. Dysfunction of
the immune system is recognized as a pathogenic mechanism
that can lead to diseases and failure of virtually every organ
system. Fortunately, advances in the prevention and treatment
of immunologic diseases also offer enhanced intervention, of-
ten before irreversible target organ damage or destruction has
occurred. Thus, clinical immunologists are frequently in the
vanguard of translating molecular medicine from the labora-
tory bench to the patient bedside.
In the United States, clinical immunologists often function
as primary care providers for patients with a wide variety of
disorders of immune function, including immune deficiency,
allergic disease, and autoimmunity. As a result, although clinical
immunology has not been constituted in this country as a for-
mal subspecialty, many influential voices in the “official” disci-
plines of allergy and rheumatology regard themselves foremost
as clinical immunologists. We trust that this textbook will prove
useful to both clinical generalists and clinical immunology
subspecialists.
The book opens with three sections dedicated to the funda-
mental sciences that underlie clinical immunology. However,
authors of the basic science chapters were asked to cast their
chapters in a context of clinical relevance. We believe this has
been accomplished. The basic science chapters are followed by
sections on Immune Deficiency and Immune Regulatory Dis-
orders; Allergic Diseases; Systemic Immune Diseases; Organ-
Specific Inflammatory Disorders; Immunology and Immuno-
therapy of Neoplasia; Medical Management of Immunologic
Diseases; Transplantation of Tissues and Organs; and the Tech-
nologies of Diagnostic Immunology.
We have preserved features in the book that were well re-
ceived in previous editions. Chapters are generously illustrated,
and all chapters contain a Key Concepts summary Box (com-
monly in bulleted form) as well as an On the Horizon box, in
which authors look to research opportunities for important
advances over the next five to ten years. Furthermore, due to
the extraordinarily cross-disciplinary nature of clinical immu-
nology, it is our hope that investigators working in one area
might find new ideas and opportunities in the On the Horizon
boxes outside their primary area of focus. Other boxes similarly
summarize content with Clinical Relevance, Clinical Pearls, and
Therapeutic Principles.
Now in its 6th edition since it was first published in 1996, this
book represents the achievements and provides access to the ex-
pertise of ~200 individual contributors. As editors, we are deep-
ly grateful for the thousands of hours of work put into this effort
by our colleagues in Clinical Immunology around the globe. We
also note the exceptional support that the preparation of this
edition has received from publishing experts at Elsevier, in par-
ticular Robin Carter, Louise Cook, Jennifer Ehlers, and Andrew
Riley. Thank you so much, Robin, Louise, Jennifer, and Andrew.
The task would have been impossible without your expertise.
Robert R. Rich
Thomas A. Fleisher
Harry W. Schroeder Jr.
Cornelia M. Weyand
David B. Corry
Jennifer M. Puck
xi
 LIST OF CONTRIBUTORS

The editors would like to acknowledge and offer grateful thanks Subash Babu, MBBS, PhD
for the input of all previous editions’ contributors, without Scientific Director
whom this new edition would not have been possible. ICER
National Institutes of Health-NIRT-ICER
Roshini Sarah Abraham, PhD Chennai, India;
Professor of Clinical Pathology; Director, Diagnostic Immunology Staff Scientist, Laboratory of Parasitic Diseases
Laboratory National Institute of Allergy and Infectious Diseases (NIAID)
Department of Pathology and Laboratory Medicine Bethesda, MA, United States
Nationwide Children’s Hospital and The Ohio State University College
Justin M. Balko, PharmD, PhD
of Medicine
Associate Professor of Medicine
Columbus, OH, United States
Associate Professor of Pathology, Microbiology and Immunology
Vanderbilt University Medical Center
Behdad Afzali, MBBS, PhD, MRCP
Nashville, TN, United States
Earl Stadtman Investigator
Kidney Diseases Branch Mark Ballow, MD
National Institute of Diabetes and Digestive and Professor of Pediatrics
Kidney Diseases Department of Pediatrics
National Insitute of Health Morsani College of Medicine
Bethesda, MD, United States St Petersburg, FL, United States;
Former Chief, Division of Allergy and Immunology
Ana Águeda, MD Department of Pediatrics
Department of Rheumatology SUNY Buffalo
Centro Hospitalar do Baixo Vouga Buffalo, NY, United States
Aveiro, Portugal
Rachel Bean, MD
Cem Akin, MD, PhD Special Volunteer
Professor of Medicine Division of Intramural Research
Division of Internal Medicine National Institute of Allergy and Infectious Diseases
University of Michigan National Institutes of Health
Ann Arbor, MI, United States Bethesda, MD, United States

Alexia Belavgeni, MSc

Cristina Albanesi, PhD
Department of Nephrology
Laboratory of Experimental Immunology
University Hospital Carl Gustav Carus
Istituto Dermopatico dell’Immacolata - Istituto di Ricovero e Cura a
Technische Universität Dresden
Carattere Scientifico (IDI-IRCCS)
Dresden, Germany
Rome, Italy
Claudia Berek, PhD
Brendan Antiochos, MD Department of B Cell Immunology
Department of Medicine Deutsches Rheuma Forschungszentrum
Johns Hopkins University Berlin, Germany
Baltimore, MD, United States
Timothy Beukelman, MD, MSCE
Cynthia Aranow, MD Associate Professor
Feinstein Institutes for Medical Research Department of Pediatrics, Division of Rheumatology
Northwell Health University of Alabama at Birmingham Heersink School
Manhasset, NY, United States of Medicine
Birmingham, AL, United States
John P. Atkinson, MD
Vivien Beziat, PhD
Department of Medicine
Assistant Professor
Washington University School of Medicine
Laboratory of Human Genetics of Infectious Diseases
St. Louis, MO, United States
Institut Imagine/University of Paris
Paris, France
Thomas M. Aune, PhD
Professor Lynn Bimler, PhD
Department of Medicine Postdoctoral Fellow
Vanderbilt University Medical Center Department of Medicine
Nashville, TN, United States Baylor College of Medicine
Houston, TX, United States
xiii
xiv List Of Contributors

J. Andrew Bird, MD Sarah K. Browne, MD

Associate Professor Medical Officer
Division of Allergy and Immunology Division of Vaccines and Related Product Applications
Department of Pediatrics Food and Drug Administration
University of Texas Southwestern Medical Center; Silver Spring, MD, United States
Director
Food Allergy Center A. Wesley Burks, MD
Children’s Medical Center Dean of the UNC School of Medicine and CEO of UNC Health
Dallas, TX, United States Vice Chancellor for Medical Affairs
University of North Carolina
Sarah E. Blutt, PhD Chapel Hill, NC, United States
Associate Professor
Molecular Virology and Microbiology Jacinta Bustamante, MD, PhD
Associate Professor Associate Professor
Molecular and Cellular Biology Human Genetics of Infectious Diseases – GHMI
Baylor College of Medicine Imagine Institute/University of Paris
Houston, TX, United States Paris, France

Mark Boguniewicz, MD
Jean-Laurent Casanova, MD, PhD
Professor, Division of Allergy-Immunology
Levy Family Professor
Department of Pediatrics
The Rockefeller University;
National Jewish Health and University of Colorado School of
Investigator
Medicine
Howard Hughes Medical Institute;
Denver, CO, United States
Head
Bertrand Boisson, PhD St. Giles Laboratory of Human Genetics of Infectious Diseases
Assistant Professor Laboratory of Human Genetics of Infectious Diseases
Laboratory of Human Genetics of Infectious Diseases Institut Imagine/University of Paris
Institut Imagine/University of Paris Paris, France
Paris, France;
St. Giles Laboratory of Infectious Diseases Alice Y. Chan, MD, PhD
The Rockefeller University Department of Pediatrics
New York, NY, United States University of California San Francisco
San Francisco, CA, United States
Stéphanie Boisson-Dupuis, PhD
St Giles Laboratory of Human Genetics of Infectious Diseases Edwin S. L. Chan, MB, ChB, FRCPC
the Rockefeller University Adjunct Associate Professor of Medicine
New York, NY, United States Department of Medicine
New York University School of Medicine
Elena Borzova, PhD New York, NY, United States
Professor
Department of Dermatology and Venereology Walter Winn Chatham, MD
I.M. First Moscow State Medical University Professor of Medicine, Clinical Immunology and Rheumatology
Moscow, Russian Federation University of Alabama at Birmingham
Birmingham, AL, United States
Maria Bottazzi, PhD
Associate Dean
Javier Chinen, MD, PhD
National School of Tropical Medicine
Allergist and Immunologist
Baylor College of Medicine
Baylor College of Medicine
Houston, TX, United States
The Woodlands, Texas Children’s Hospital
Prosper N. Boyaka, PhD Humble, TX, United States
Professor
Veterinary Biosciences Lisa Christopher-Stine, MD
The Ohio State University Assistant Professor of Pathology and Laboratory Medicine
Columbus, OH, United States University of Rochester Medical Center
Rochester, NY, United States
John M. Bridges, MD
Associate and Fellow, Clinical Immunology and Rheumatology Emily Coates, PhD
Children’s Hospital of Alabama Director of Translational Science
University of Alabama at Birmingham Clinical Trials Program
Birmingham, AL, United States Vaccine Research Center
National Institute of Allergy and Infectious Diseases
Bethesda, MD, United States

Andrew P. Cope, BSc, MBBS, PhD, FRCP
Centre for Rheumatic Diseases
King’s College London
London, UK
David B. Corry, MD
Professor
Medicine and Pathology and Immunology
Baylor College of Medicine
Houston, TX, United States
Joana Cosme, MD
Allergy and Clinical Immunology Consultant
Department of Immunoallergology
Centro Hospitalar Universitário de Lisboa Norte
Lisbon, Portugal
Randy Q. Cron, MD, PhD
Professor of Pediatrics and Medicine
University of Alabama at Birmingham;
Director of Pediatric Rheumatology
Children’s of Alabama
Birmingham, AL, United States
Marinos C. Dalakas, MD, FAAN
Professor of Neurology
Chief Neuromuscular Division
Department of Neurology
Thomas Jefferson University
Philadelphia, PA, United States
Sara M. Dann, PhD
Assistant Professor
Internal Medicine
University of Texas Medical Branch
Galveston, TX, United States
Satya Das, MD, MSCI
Assistant Professor
Medicine
Vanderbilt University Medical Center
Nashville, TN, United States
Molly M. Daughety, MD
Physician
Hematology Oncology
Duke University Medical Center
Durham, NC, United States
Betty Diamond, MD
Feinstein Institutes for Medical Research
Northwell Health
Manhasset, NY, United States
Angela Dispenzieri, MD
Professor of Medicine and Laboratory Medicine
Mayo Clinic
Rochester, MN, United States
List Of Contributors xv
Stephen R. Durham, MA, MD, FRCP
Professor of Allergy and Respiratory Medicine
Allergy and Clinical Immunology
NHLI, Imperial College London
London, UK
Todd N. Eagar, PhD
Assistant Professor
Pathology and Genomic Medicine
Houston Methodist Hospital Research Institute
Director of HLA and Transplant Immunology Laboratory
Pathology and Genomic Medicine
Houston Methodist Hospital
Houston, TX, United States;
Assistant Professor
Laboratory Medicine
Weill Cornell Medical College
New York, NY, United States
Michelle Al-Hosni, MD
Allergy and Clinical Immunology Fellow
University of Michigan
Ann Arbor, MI, United States
Sarah Elitzur, MD
Senior Physician
Pediatric Hematology-Oncology
Schneider Children’s Medical Center
Petah Tikva, Israel
Craig A. Elmets, MD
Professor and Chair
Dermatology
University of Alabama at Birmingham
Birmingham, AL, United States
Doruk Erkan, MD
Associate Professor
Rheumatology
Hospital for Special Surgery
New York, NY, United States
Thomas A. Fleisher, MD
Executive Vice President
American Academy of Allergy, Asthma and Immunology
Milwuakee, WI, United States;
Scientist Emeritus, National Institutes of Health Clinical Center
Bethesda, MD, United States
Luz Fonacier, MD
Professor of Medicine
Department of Medicine
NYU Long Island School of Medicine;
Head of Allergy
Department of Medicine
NYU Langone Hospital, Long Island;
Training Program Director
Allergy and Immunology
Department of Medicine
NYU Langone Hospital, Long Island
Mineola, NY, United States
xvi List Of Contributors

Andrew P. Fontenot, MD Moshe E. Gatt, MD

Professor of Medicine Senior Hematologist
Department of Medicine Hematology
University of Colorado Anschutz Medical Campus Hadassah Hebrew University Medical Center
Aurora, CO, United States Jerusalem, Israel

George Fragoulis, MD, PhD M. Eric Gershwin, MD, PhD

Rheumatologist Chief Division of Rheumatology Allergy and Clinical Immunology
Institute of Infection, Immunity and Inflammation Department of Internal Medicine
University of Glasgow University of California
Glasgow, UK; Davis, CA, United States
First Propedeutic Internal Medicine
National and Kapodistrian University of Athens Susan L. Gillespie, MD, PhD
Athens, Greece Associate Professor
Pediatrics
Ivo M. B. Francischetti, MD, PhD Baylor College of Medicine
Hematopathology Fellow Houston, TX, United States
Laboratory of Pathology
National Institutes of Health Lynn K. Gordon, MD, PhD
Bethesda, MD, United States Professor Emeritus
Department of Ophthalmology
Tilo Freiwald, MD David Geffen School of Medicine at UCLA
Research Fellow Los Angeles, CA, United States
Immunoregulation Section
Kidney Diseases Branch Jörg J. Goronzy, MD, PhD
National Institute of Diabetes and Digestive and Kidney Diseases Department of Medicine
National Institutes of Health Mayo Clinic College of Medicine and Science
Bethesda, MD, United States Rochester, MN, United States

Clive E. H. Grattan, MA, MD, FRCP

Anthony J. Frew, MD, FRCP†
Consultant Dermatologist
Professor of Allergy and Respiratory
St. John’s Institute of Dermatology
Medicine
London, UK
Department of Respiratory Medicine
Royal Sussex County Hospital
Neil S. Greenspan, MD, PhD
Brighton, UK
Professor of Pathology
University Hospitals Cleveland Medical Center
Kohtaro Fujihashi, DDS, PhD
Case Western Reserve University
Project Professor
Cleveland, OH, United States
Division of Clinical Vaccinology International Research and
Development Center for Mucosal Vaccines Anna Gschwend, MD, PhD
The Institute of Medical Science The University of Tokyo Allergology/Immunology Specialist
Tokyo, Japan; University Clinic for Pulmonary Medicine and Allergology
Professor Emeritus Inselspital/University Hospital
Pediatric Dentistry Bern, Switzerland
The University of Alabama at Birmingham
Birmingham, AL, United States Claire E. Gustafson, PhD
Scientist III
Massimo Gadina, PhD Allen Institute for Immunology
Chief Seattle, WA, United States
Translational Immunology Section
National Institute of Arthritis and Musculoskeletal and Skin Diseases Tillie-Louise Hackett, PhD
National Institutes of Health Professor
Bethesda, MD, United States Anesthesiology, Pharmacology and Therapeutics
Centre for Heart Lung Innovation
Laurent Gapin, PhD University of British Columbia
Professor Vancouver, BC, Canada
Department of Immunology and Microbiology
University of Colorado Anschutz Medical Campus Robert G. Hamilton, PhD, DABMLI
Aurora, CO, United States; Professor
Department of Immunology and Genomic Medicine Medicine and Pathology
National Jewish Health Johns Hopkins University School of Medicine
Denver, CO, United States Baltimore, MD, United States
 List Of Contributors xvii

Myra Happe, PhD Katherine Houser, PhD

Scientific Advisor Senior Scientific Advisor
Clinical Trials Program, Vaccine Research Center NationaI Institutes of Health
National Institute of Allergy and Infectious Diseases Bethesda, MD, United States
National Institutes of Health
Bethesda, MD, United States Nicholas D. Huntingdon, BSc, PhD
Laboratory Head
Leonard C. Harrison, MB, BS, MD, DSc, DMedSci, FRACP, Department of Biochemistry and Molecular Biology
FRCPA, FAHMS Monash University
Professor Clayton, VIC, Australia
Population Health and Immunity Division
Walter and Eliza Hall Institute of Medical Research Tracy Hwangpo, MD, PhD
Parkville, Melbourne, VIC, Australia; Instructor of Medicine
Professor Department of Medicine
Medical Biology University of Alabama at Birmingham
University of Melbourne Birmingham, AL, United States
Melbourne, VIC, Australia
Shai Izraeli, MD
Arthur Helbling, MD Chair
Professor; Head of the Allergology and Clinical Immunology Pediatric Hematology and Oncology
Policlinic University Clinic for Pulmonary Medicine and Allergology Schneider Children’s Medical Center of Israel
Inselspital/University Hospital Petach Tikva, Israel
Bern, Switzerland
Elaine S. Jaffe, MD
Emmaline Heckmann Head, Hematopathology Section
Research Scientist Laboratory of Pathology
Department of Molecular Virology and Microbiology National Cancer Institute
Baylor College of Medicine National Institutes of Health
Houston, TX, United States Bethesda, MD, United States

Sirpa Jalkanen, MD, PhD

Kristin Hogquist, PhD
Professor
Professor
MediCity
Center for Immunology
University of Turku
University of Minnesota
Turku, Finland
Minneapolis, MN, United States
Anuja Java, MD
Tobias M. Hohl, MD, PhD
Assistant Professor of Medicine
Member
Department of Internal Medicine
Department of Medicine
Washington University School of Medicine in St. Louis;
Memorial Sloan Kettering Cancer Center
Assistant Professor of Medicine
New York, NY, United States
Department of Internal Medicine
Veterans Affairs Medical Center
Steven M. Holland, MD St Louis, MO, United States
Director
Division of Intramural Research Douglas B. Johnson, MD, MSCI
National Institute of Allergy and Infectious Diseases Associate Professor of Medicine
National Institutes of Health (NIH) Department of Medicine
Chief Vanderbilt University Medical Center
Immunopathogenesis Section Nashville, TN, United States
National Institute of Allergy and Infectious Diseases
National Institutes of Health (NIH) Tory P. Johnson, PhD
Bethesda, MD, United States Department of Neurology
Johns Hopkins University
Peter J. Hotez, MD, PhD Baltimore, MD United States
Dean, National School of Tropical Medicine
Professor, Pediatrics and Molecular and Virology and Microbiology Michael B. Jordan, MD
Head, Section of Pediatric Tropical Medicine Professor
Baylor College of Medicine; Pediatrics, Divisions of Immunobiology and Bone Marrow
Director, Sabin Vaccine Institute Texas Children’s Hospital Center for Transplantation and Immune Deficiency
Vaccine Development University of Cincinnati
Houston, TX, United States Cincinnati Children’s Hospital
Cincinnati, OH, United States
xviii List Of Contributors

Shyam R. Joshi, MD Donald B. Kohn, MD

Assistant Professor of Medicine Professor
Section of Allergy and Immunology Microbiology, Imunology and Molecular Genetics
Oregon Health and Science University University of California, Los Angeles
Portland, OR, United States Los Angeles, CA, United States

Emmanuelle Jouanguy, PhD Michihito Kono, MD, PhD

Associate Professor Assistant Professor
Laboratory of Human Genetics of Infectious Diseases Department of Rheumatology, Endocrinology and Nephrology
Imagine Institute/University of Paris Faculty of Medicine
Paris, France Hokkaido University
Sapporo, Japan
Henry J. Kaminski, MD
Chairman, Neurology Robert Korngold, PhD
George Washington University Emeritus Member
Washington, DC, United States Center for Discovery and Innovation
Hackensack Meridian Health
Stefan H. E. Kaufmann, PhD Nutley, NJ, United States
Professor and Director Emeritus
Max Planck Institute for Infection Biology Vasiliki Koulouri, MD, MSc
Berlin, Germany PhD Student
Department of Physiology
David A. Khan, MD National and Kapodistrian University of Athens
Professor of Medicine and Pediatrics School of Medicine
Division of Allergy and Immunology Athens, Greece
University of Texas Southwestern Medical Center
Dallas, TX, United States
Douglas B. Kuhns, PhD
Principal Scientist
Farrah Kheradmand, MD Neutrophil Monitoring Lab
Professor Applied/Developmental Research Directorate
Pathology, Immunology, Medicine Frederick National Laboratory for Cancer Research
Baylor College of Medicine Frederick, MD, United States
Houston, TX, United States

Hrishikesh S. Kulkarni, MD, MSCI

Dilawar Singh Khokar, MD
Instructor
Allergy and Clinical Immunology Fellow
Medicine, Division of Pulmonary and Critical Care Medicine
University of Michigan
Washington University School of Medicine
Ann Arbor, MI, United States
St. Louis, MO, United States

Paneez Khoury, MD MHSc

Caroline Y. Kuo, MD
Human Eosinophil Section
Division of Allergy and Immunology
Laboratory of Parasitic Diseases
Department of Pediatrics
National Institute of Allergy and Infectious Diseases
David Geffen School of Medicine at UCLA
National Institutes of Health
Los Angeles, CA, United States
Bethesda, MD United States

Linda L. Kusner, PhD

Bruce S. Klein, MD
Associate Research Professor
Gerard B. Odell Professor and Shirley S. Matchette Professor
Pharmacology and Physiology
Department of Pediatrics;
George Washington University
University of Wisconsin, Madison;
Washington, DC, United States
Professor, Internal Medicine;
Professor, Internal Medicine, Medical Microbiology and Immunology
University of Wisconsin, Madison Arash H. Lahouti, MD
Madison, WI, United States Assistant Professor of Pathology and Laboratory Medicine
University of Rochester Medical Center
Amy D. Klion, MD Rochester, NY, United States
Human Eosinophil Section
Laboratory of Parasitic Diseases, National Institute of Allergy and Laura C. Lane, MD
Infectious Diseases Gynecologist
National Institutes of Health Sky Ridge Medical Center
Bethesda, MD, United States Lone Tree, CO, United States
 List Of Contributors xix

Arian Laurence, PhD, MRCP, FRCPath Andrew H. Lichtman, MD, PhD

Visiting Research Fellow Professor of Pathology
Nuffield Department of Medicine Brigham and Women’s Hospital;
Oxford University Professor of Pathology, Harvard Medical School
Oxford, UK; Boston, MA, United States
Clinical Research Fellow
Institute of Cellular Medicine Andreas Linkermann, MD
University of Newcastle Professor
Newcastle upon Tyne, UK Department of Nephrology
University Clinic Carl Gustav Carus
Joyce S. Lee, MD Dresden, Saxony, Germany
Associate Professor
Department of Medicine Michail S. Lionakis, MD, DSc
University of Colorado Anschutz Medical Campus Chief, Fungal Pathogenesis Section
Aurora, CO, United States Deputy Chief, Laboratory of Clinical Immunology and Microbiology
National Institute of Allergy and Infectious Diseases (NIAID)
S. Thera Lee, PhD National Institutes of Health (NIH)
Professor Bethesda, MD, United States
Center for Immunology University of Minnesota
Minneapolis, MN, United States
M. Kathryn Liszewski, PhD
Donald Y. M. Leung, MD, PhD Assistant Professor of Medicine
Edelstein Family Chair of Pediatric Allergy-Immunology Medicine/Rheumatology
Department of Pediatrics Washington University School of Medicine
National Jewish Health St. Louis, MO, United States
Professor of Pediatrics
Department of Pediatrics Michael D. Lockshin, MD
University of Colorado Medical School Director, Barbara Volcker Center
Denver, CO, United States Hospital for Special Surgery
Weill Cornell Medical College
Ofer Levy, MD, PhD New York, NY, United States
Director, Precision Vaccines Program
Division of Infectious Diseases Debra Long Priel, MS
Boston Children’s Hospital; Clinical Services Program
Professor of Pediatrics Leidos Biomedical Research, Inc.
Harvard Medical School Frederick, MD, United States
Boston, MA, United States;
Associate Member
Adi Zoref Lorenz, MD
Broad Institute of MIT and Harvard
Instructor
Cambridge, MA, United States
Hematology Institute
Dorothy E. Lewis, PhD, MS Meir Medical Center
Research Scientist Sackler Faculty of Medicine
Faculty Development Tel Aviv, Israel;
Houston Methodist Research Institute; Division of Immunobiology
Adjunct Professor Cincinnati Children’s Hospital
Pathology and Immunology Cincinnati, OH, USA
Baylor College of Medicine;
Adjunct Professor Ralf J. Ludwig, MD
Internal Medicine Professor
University of Texas Health Science Center Lübeck Institute of Experimental Dermatology
Houston, TX, United States University of Lübeck
Lübeck, Germany
Evan Li, MD
Assistant Professor Amber Luong, MD, PhD
Department of Medicine Professor
Baylor College of Medicine Otorhinolaryngology - Head and Neck Surgery
Houston, TX, United States McGovern Medical School of The University of
Texas Health Science Center
Peter Libby, MD Houston, TX, USA
Cardiovascular Specialist
Cardiovascular Medicine Raashid Ahmed Luqmani, MD
Brigham and Women’s Hospital/Harvard Medical School Oxford NIHR Biomedical Research Centre University of Oxford
Boston, MA, United States Oxford, UK
xx List Of Contributors

Meggan Mackay, MD, MS Françoise Meylan, PhD

Feinstein Institutes for Medical Research National Institute of Arthritis and Musculoskeletal and Skin Diseases
Northwell Health National Institutes of Health
Manhasset, NY, United States Translational Immunology Section
Bethesda, MD, USA
Alfred Mahr, MD, MPH, PhD
Professor Stephen D. Miller, PhD
Clinic for Rheumatology Professor
Kantonsspital St. Gallen Department of Microbiology-Immunology
St. Gallen, Switzerland Northwestern University Medical School
Chicago, IL, United States
Tamir Malley, MD
Royal Brompton Hospital Anna L. Mitchell, MBBS, MRes, PhD
London, UK Consultant Endocrinologist
Department of Endocrinology
Elinor C. Mannon, MD Newcastle upon Tyne NHS Hospitals Foundation Trust
Department of Physiology Newcastle upon Tyne, UK
Medical College of Georgia at Georgia Regents University
Augusta, GA, United States Dimitri S. Monos, PhD
Professor
Peter J. Mannon, MD Pathology and Laboratory Medicine
Professor of Medicine Perelman School of Medicine
Chief, Division of Gastroenterology and Hepatology University of Pennsylvania
University of Nebraska Medical Center Children’s Hospital of Philadelphia
Omaha, NE, United States Philadelphia, PA, United States

Roslyn B. Mannon, MD Scott N. Mueller, PhD

Professor of Medicine, Pathology and Microbiology Professor
University of Nebraska Medical Center Microbiology and Immunology
Omaha, NE, United States The University of Melbourne
Melbourne, VIC, Australia
Michael P. Manns, MD
Hannover Medical School Catharina M. Mulders-Manders, MD, PhD
Hannover, Germany Infectious Diseases Specialist
Department of Internal Medicine
Anthony Maresso, PhD Infectious Disease Section
Associate Professor Radboudumc Expertise Centre for Immunodeficiency and
Virology and Microbiology Autoinflammation
Baylor College of Medicine Radboud University Medical Centre
Houston, TX, United States Nijmegen, The Netherlands

Scott M. Matson, MD Pashna N. Munshi, MD

Assistant Professor Associate Clinical Director
Pulmonary, Critical Care and Sleep Medicine Stem Cell Transplant and Immunotherapy Program
University of Kansas Lombardi Comprehensive Cancer Center
Kansas City, KS, United States Washington, DC, United States

Clio P. Mavragani, MD, PhD Philip M. Murphy, MD

Assistant Professor Chief, Laboratory of Molecular Immunology
Department of Physiology National Institute of Allergy and Infectious Diseases
National and Kapodistrian University of Athens National Institutes of Health
Athens, Greece Bethesda, MD, United States

Craig L. Maynard, PhD Pierre Noel, MD

Assistant Professor Professor of Medicine
Pathology and Medicine Division of Hematology-Oncology
University of Alabama at Birmingham Mayo College of Medicine
Birmingham, AL, United States Scottsdale, AZ, USA

Douglas R. McDonald, MD, PhD Luigi D. Notarangelo, MD

Assistant Professor in Pediatrics Chief, Laboratory of Clinical Immunology and Microbiology
Immunology National Institute of Allergy and Infectious Diseases (NIAID)
Boston Children’s Hospital National Institutes of Health (NIH)
Boston, MA, United States Bethesda, MD, United States
 List Of Contributors xxi

Cristiane J. Nunes-Santos, MD Simon H. S. Pearce, MD

Postdoctoral Visiting Fellow Professor of Endocrinology
Department of Laboratory Medicine Newcastle University Medical School
National Institutes of Health Clinical Center Newcastle upon Tyne, England
Bethesda, MD, United States
Erik J. Peterson, MD
Robert L. Nussbaum, MD
Associate Professor of Medicine
Chief Medical Officer
Division of Rheumatic and Autoimmune Diseases
Medical Affairs
University of Minnesota
Invitae Corporation;
Minneapolis, MN, United States
Volunteer Clinical Faculty
Department of Medicine
University of California San Francisco Stefania Pittaluga, MD, PhD
San Francisco, CA, United States Staff Clinician
Laboratory of Pathology
Thomas B. Nutman, MD National Cancer Institute Bethesda
Chief, Laboratory of Parasitic Diseases National Institutes of Health
National Institute of Allergy and Infectious Diseases; Bethesda, MD, United States
Head, Clinical Parasitology Section
Laboratory of Parasitic Diseases Francesca Polverino, MD, PhD
National Institute of Allergy and Infectious Diseases; Associate Professor of Medicine
Head, Helminth Immunology Section Pulmonary and Critical Care Medicine
Laboratory of Parasitic Diseases Baylor College of Medicine
National Institute of Allergy and Infectious Diseses Neurosensory Center of Houston
Bethesda, MD, United States Houston, TX, United States

Stephen L. Nutt, BSc, PhD

Laboratory Head, Immunology Division Jennifer M. Puck, MD
The Walter and Eliza Hall Institute of Medical Research Professor
Parkville, VIC, Australia Department of Pediatrics
University of California San Francisco
Lorraine O’Neill, MD San Francisco, CA, United States
The EULAR Centre for Arthritis and Rheumatic Disease
St. Vincent’s University Hospital Anne Puel, PhD
Elm Park and University College Dublin Professor
Dublin, Ireland Laboratory of Human Genetics of Infectious Diseases
Institut Imagine/University of Paris
John J. O’Shea, MD Paris, France
Director, NIAMS Intramural Research Program
National Institutes of Health (NIH) Andreas Radbruch, MD, PhD
Bethesda, MD, United States Scientific Director
Deutsches Rheuma-Forschungszentrum Berlin
Thomas L. Ortel, MD, PhD A Leibniz Institute;
Professor Professor for Experimental Rheumatology
Departments of Medicine and Pathology Charité – Universitätsmedizin Berlin
Duke University Medical Center Berlin, Germany
Durham, NC, United States
Raja Rajalingam, PhD
Professor of Clinical Surgery and Director of Immunogenetics and
Sung-Yun Pai, MD Transplantation Laboratory
Senior Investigator Department of Surgery
Immune Deficiency Cellular Therapy Program University of California San Francisco
Center for Cancer Research, National Cancer Institute San Francisco, CA, United States
National Institutes of Health
Bethesda, MD, USA Stephen T. Reece, PhD
Director, Antimicrobial Antibodies and Vaccines
Mary E. Paul, MD Kymab Ltd.
Professor of Pediatrics Cambridge, UK
Baylor College of Medicine
Houston, TX, United States John D. Reveille, MD
Professor and Director, Rheumatology
University of Texas Health Science Center at Houston
Houston, TX, United States
xxii List Of Contributors

Robert R. Rich, MD Umit Murat Sahiner, MD

Dean and Professor Emeritus Professor
Medicine Pediatric Allergy
University of Alabama at Birmingham Hacettepe University
Former Senior Vice President for Medicine Ankara, Turkey;
School of Medicine Academic Visitor
University of Alabama at Birmingham Allergy and Clinical Immunology
Birmingham, AL, United States Imperial College
London, UK
Lauren K. Ridley, MD
Department of Internal Medicine Shimon Sakaguchi, MD, PhD
Division of Rheumatology Laboratory of Experimental Immunology
McGovern Medical School at The University of WPI Immunology Frontier Research Center
Texas Health Science Center Osaka University, Suita
Houston, TX, USA Osaka, Japan

Whitney Salinas, MD
Andrew R. Romeo, MD Allergy and Immunology
Clinical Assistant Professor Park Lane Allergy and Asthma Center
Department of Neurology Baylor University Medical Center
University of Michigan Dallas, TX, United States
Ann Arbor, MI, United States
Marko Salmi, MD, PhD
Cliona M. Rooney, PhD Professor
Professor MediCity Research Laboratory
Departments of Pediatrics, Pathology, and Molecular University of Turku
Virology and Microbiology Turku, Finland
Center for Cell and Gene Therapy
Baylor College of Medicine Sarah W. Satola, PhD
Houston, TX, United States Associate Professor
Medicine/Infectious Diseases
Emory University School of Medicine
Antony Rosen, MBChB, BSc (Hons) Atlanta, GA, United States
Mary Betty Stevens Professor of Medicine, Professor of Pathology
Director, Division of Rheumatology; Marcos C. Schechter, MD
Department of Medicine Assistant Professor
Vice Dean for Research Department of Medicine
School of Medicine Emory University School of Medicine
Johns Hopkins University Atlanta, GA, United States
Baltimore, MD, United States
Enno Schmidt, MD, PhD
Sergio D. Rosenzweig, MD, PhD Professor and Director
Chief, Immunology Service Lübeck Institute of Experimental Dermatology (LIED);
Department of Laboratory Medicine Clinical Center Senior Consultant
National Institutes of Health Department of Dermatology
Bethesda, MD, United States University of Lübeck
Lübeck, Germany
Barry T. Rouse, DVM, PhD, DSc
Distinguished Professor Harry W. Schroeder Jr., MD, PhD
Biomedical and Diagnostic Sciences Professor
University of Tennessee Division of Clinical Immunology and Rheumatology
Knoxville, TN, United States Departments of Medicine, Microbiology, and Genetics
University of Alabama at Birmingham
Scott D. Rowley, MD Birmingham, AL, United States
Associate Clinical Director
Stem Cell Transplant and Cellular Immunotherapy Program Pamela L. Schwartzberg, MD PhD
Lombardi Comprehensive Cancer Center; Senior Investigator
Assistant Professor of Medicine Laboratory of Immune System Biology
Georgetown University School of Medicine National Institutes of Allergy and Infectious Diseases
Washington, DC, United States National Human Genome Research Institute
National Institutes of Health
Bethesda, MD, United States
 List Of Contributors xxiii

Giuseppe Sciumè, PhD Joo Y. Song, MD

Laboratory Affiliated to Istituto Pasteur Italia – Fondazione Associate Clinical Professor
Cenci-Bolognetti Department of Pathology
Department of Molecular Medicine City of Hope National Medical Center
Sapienza University of Rome Duarte, CA, United States
Rome, Italy
David S. Stephens, MD
Benjamin M. Segal, MD Vice President for Research
Chair Robert W. Woodruff Health Sciences Center
Department of Neurology; Emory University;
Director Stephen W. Schwarzmann Distinguished Professor of Medicine;
Neurological Research Institute; Chair, Department of Medicine
Professor Emory University School of Medicine
Department of Neurology Atlanta, GA, United States
The Ohio State University
Columbus, OH, United States Robin Stephens, PhD
Associate Professor
Carlo Selmi, MD Department of Internal Medicine
Professor Division of Infectious Diseases
Rheumatology and Clinical Immunology University of Texas Medical Branch
Humanitas Research Hospital/Humanitas University Galveston, TX, United States
Rozzano, Italy
Michel M. Sun, MD, PhD
Amir Sharabi, MD, PhD Resident
Senior Rheumatologist Department of Ophthalmology
Rheumatology University of California Los Angeles
Rabin Medical Center Los Angeles, CA, United States
Petach-Tikva, Israel;
Assistant Professor Benedetta Terziroli Beretta-Piccoli, MD
Microbiology and Immunology Associate Professor
Sackler Faculty of Medicine Epatocentro Ticino;
Tel-Aviv University Facoltà di Scienze Biomediche
Tel-Aviv, Israel Università della Svizzera Italiana
Lugano, Switzerland;
Kristin Ammon Shimano, MD Institute of Liver Studies
HS Associate Clinical Professor King’s College London Faculty of Life Sciences and Medicine at
Pediatrics King’s College Hospital
UCSF Benioff Children’s Hospital London, UK
San Francisco, CA, United States
Wulf Tonnus, MD
Patricia M. Sikorski, PhD Department of Nephrology
Postdoctoral Scientist University Hospital Carl Gustav Carus
Pharmacology and Physiology Technische Universität Dresden
George Washington University Dresden, Germany
Washington, DC, United States
Troy R. Torgerson, MD, PhD
Anna Simon, MD, PhD Director of Experimental Immunology
Associate Professor Allen Institute for Immunology
Internal Medicine, Section Infectious Diseases Seattle, WA, United States
Radboudumc Expertise Centre for Immunodeficiency and
Raul Martin Torres, MS, PhD
Autoinflammation
Professor
Radboud Universitary Medical Centre
Immunology and Microbiology
Nijmegen, The Netherlands
University of Colorado School of Medicine;
Professor
Gideon P. Smith, MD, PhD, MPH Department of Biomedical Research
Vice Chair National Jewish Health
Dermatology Aurora, CO, United States
Massachusetts General Hospital/Harvard Medical School
Boston, MA, United States
xxiv List Of Contributors

Jennifer D. Treat, PA-C, MSHS, MPH Peter Weiser, MD

Physician Assistant Associate Professor
National Institutes of Health Department of Pediatrics, Division of
National Institute of Allergy and Infectious Diseases (NIAID) Rheumatology
Bethesda, MD, United States University of Alabama at Birmingham Heersink School of
Medicine
George C. Tsokos, MD Birmingham, AL, United States
Chief
Division of Rheumatology and Clinical Immunology Cornelia M. Weyand, MD, PhD
Beth Israel Deaconess Medical Center; Professor Emerita
Professor of Medicine Medicine
Harvard Medical School Stanford University
Boston, MA, United States Stanford, CA, United States;
Professor
Gülbü Uzel, MD Medicine and Immunology
Staff Clinician Mayo Clinic Alix School of Medicine
National Institute of Allergy and Infectious Diseases (NIAID) Rochester, MN, United States
National Institutes for Health
Bethesda, MD, United States Fredrick M. Wigley, MD
Martha McCrory Professor of Medicine
Jude E. Uzonna, DVM, PhD Division of Rheumatology
Professor of Immunology Johns Hopkins University School of Medicine
University of Manitoba Baltimore, MD, United States
Winnipeg, MB, Canada
James B. Wing, PhD
Laboratory of Experimental Immunology
Jeroen C. H. van der Hilst, MD, PhD Immunology Frontier Research Center
Infectious Disease Specialist Osaka University
Infectious Diseases and Immunity Suita, Osaka, Japan
Jessa Hospital;
Associate Professor Immune Pathology Kathryn J. Wood, DPhil
Limburg Clinical Research Centre Professor Emerita of Immunology
University of Hasselt Nuffield Department of Social Sciences
Hasselt, Belgium University of Oxford
Oxford, UK
Jos W. M. van der Meer, MD, PhD
Professor of Medicine Shyra Wilde, PhD
Department of Internal Medicine Department of Microbiology and Immunology
Radboud University Medical Centre Emory University School of Medicine
Nijmegen, The Netherlands Atlanta, GA USA

Hui Xu, PhD

John Varga, MD Professor
John and Nancy Hughes Professor Dermatology
Department of Medicine University of Alabama at Birmingham
Northwestern University Feinberg School of Medicine Birmingham, AL, United States
Chicago, IL, United States
Nabiha Yusuf, PhD
Meryl Waldman, MD Associate Professor
Senior Research Physician Department of Dermatology
Immunoregulation Section University of Alabama at Birmingham
Kidney Diseases Branch Birmingham, AL, United States
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health Christa S. Zerbe, MD, MS
Bethesda, MD, United States Medical Director
Clinical Patient Services Unit
Jill Weatherhead, MD, PhD Laboratory of Clinical Immunology and Microbiology
Assistant Professor The National Institutes of Health
Medicine-Pediatrics Bethesda, MD, United States
Infectious Diseases and Tropical Medicine
Baylor College of Medicine’s National School of Tropical Medicine
Houston, TX, United States
 List Of Contributors xxv

Qian Zhang, MD Shen-Ying Zhang, MD, PhD

Assistant Professor Associate Professor
Laboratory of Human Genetics of Infectious Diseases Laboratory of Human Genetics of Infectious Diseases
Institut Imagine/University of Paris Institut Imagine/University of Paris
Paris, France; Paris, France;
St. Giles Laboratory of Infectious Diseases St. Giles Laboratory of Infectious Diseases
The Rockefeller University The Rockefeller University
New York, NY, USA New York, NY, USA

Dina Ben-Yehuda, MD Arthur W. Zieske, MD

Department of Hematology Associate Professor of Clinical Pathology and
Hadassah-Hebrew University Medical Center Genomic Medicine
Jerusalem, Israel Houston Methodist Academic Institute
Houston Methodist Hospital
Weill Cornell Medical College
Houston, TX, United States
 D E D I C AT I O N

To my wife, Susan Rich

Robert R. Rich

To my wife Mary Fleisher, my partner and supporter for >50 years

Thomas A. Fleisher

To Dixie Lee Schroeder; Harry W. Schroeder III, MD, PhD; Maria Isabel, Anabel and William Schroeder;
Jeff, Elena, Liam, Noah, Haddie and Ellie Beck; and Jeannette Schroeder
Harry W. Schroeder Jr.

To Jörg Goronzy and Dominic and Isabel Weyand Goronzy

Cornelia M. Weyand

To my immunology mentors: Mary, Rich, and Farrah

David B. Corry

To Bob Nussbaum, my husband and best friend

Jennifer M. Puck

xxvii
 1
The Human Immune Response
Robert R. Rich and Randy Q. Cron
Clinical immunology is a medical subspecialty largely focused
on a specific physiologic process, inflammation, which is es-
sential to good health, particularly in defense against patho-
genic organisms, recovery from injury, and containment of
neoplasms. However, inflammation, which is mediated by the
cells and soluble products of the immune system, is also a pow-
erful contributor to the pathogenesis of diseases that affect vir-
tually every organ system. A consequent challenge for clinical
immunologists, both clinicians and basic scientists, is to reduce
a dizzying array of disease descriptions to a systematic under-
standing of pathogenic mechanisms in order to facilitate trans-
lation of fundamental concepts and new discoveries into more
effective disease prevention or treatment.
This introductory chapter is directed to nonimmunologist
clinicians and researchers. It is structured as an introduction to
the interacting elements of the human immune system and their
disordered functions in diseases. The subtleties, including im-
munologic or molecular genetic jargon unavoidably used, are
described in detail in the chapters that follow.
THE HOST-MICROBE INTERACTION
The vertebrate immune system is a product of eons of evolu-
tionary relationships between rapidly evolving microbial organ-
isms and their much less rapidly reproducing, and hence less
adaptable, hosts.1 In general, the relationship is mutually ben-
eficial, each providing nutrients and other materials essential to
the well-being of their partner—the host and its microbiome
(Chapter 22). Occasionally, however, a normally beneficial re-
lationship becomes pathologic. Pathogenic microbes can over-
whelm the microbiome, invade host tissues, and result in host
morbidity or even death. Because the vertebrate host cannot
win a battle with microbial invaders by rapid mutation and se-
lection, the immune system uses a strategy of complexity and
redundancy, which involves both the individual organism and
its collective population.
Reflecting plasticity of the response, specific defenses differ,
depending on the nature of the infectious agent and its point
of entry and distribution within the body. Regardless of the
defense mechanism, an intended outcome is destruction or
neutralization of the invading organism. However, a secondary
consequence can be collateral damage to host cells. These un-
fortunate cells can be targeted for damage because they are sites
of microbial residence and replication, or they can be damaged
as “innocent bystanders.” Depending on the site and severity of
the host's defensive response, it may be accompanied by local
and/or systemic symptoms and signs of inflammation, which
may lead to long-lasting tissue dysfunction as a result of tissue
remodeling and partial repair.
2
Adaptive and Innate Immunity
Immune responses are traditionally classified as adaptive (also
termed acquired or specific) and innate (or nonspecific) (Table 1.1).
The adaptive immune system, present uniquely in species of
the phylum Chordata, is specialized for development of an in-
flammatory response based on recognition of specific “foreign”
macromolecules that are predominantly, but not exclusively,
proteins, peptides, and carbohydrates. The vast majority of
chordate species are jawed vertebrates, and this book addresses
adaptive immunity of that subphylum. Its primary effectors are
antibodies, B lymphocytes, T lymphocytes, innate lymphoid
cells (ILCs), and antigen-presenting cells (APCs). T and B lym-
phocytes express surface antigen receptors that are clonally spe-
cific as a consequence of receptor-gene rearrangements. Expan-
sion of clones of lymphocytes specific for any particular antigen
is induced by antigen encounter and consequent activation and
proliferation, thereby constituting the basis of immunologic
memory.
Innate immune responses are phylogenetically far more an-
cient, being widely represented in multicellular phyla.2 Rather
than being based on exquisitely specific recognition of a diverse
array of macromolecules (i.e., antigens), they are focused on
recognition of common molecular signatures of microbial or-
ganisms that are not present in vertebrates (Chapter 3).3 Among
these structures, which are termed pathogen-associated molecu-
lar patterns (PAMPs) or danger-associated molecular patterns
(DAMPs), are bacterial cell wall constituents, such as mannose-
rich oligosaccharides, lipopolysaccharides, peptidoglycans, and
several nucleic acid variants, including double-stranded RNA
and unmethylated CpG DNA. For both innate and adaptive im-
mune responses, defense effector mechanisms can require either
direct cell-to-cell contact or the activity of cytokines (Chapter
14) and chemokines (Chapter 15), which are hormone-like sol-
uble molecules that act in the cellular microenvironment (cell-
mediated immunity). Most immune responses include partici-
pation of both modes of response.2–4
The elements of innate immunity are diverse. They include
physical barriers to pathogen invasion (e.g., skin, mucous mem-
branes, cilia, and mucus), as well as an array of cellular and solu-
ble factors that can be activated by secreted or cell surface prod-
ucts of the pathogen, including PAMPs. Recognition of PAMPs
by cells in innate immunity, which also commonly function
as APCs to the lymphocytes of adaptive immunity, is via cell
membrane or cytoplasmic receptors known as pattern recogni-
tion receptors (PRRs). PRRs can be either membrane bound or
cytoplasmic. Membrane-bound PRRs include Toll-like recep-
tors (TLRs) and C-type lectin receptors (CLRs). Humans ex-
press 10 distinct TLRs, which recognize (among others) specific
bacterial glycolipids, lipopolysaccharide; viral single-stranded
 CHAPTER 1 The Human Immune Response
TABLE 1.1 Features of Innate and
Adaptive Immune Systems
Distinguishing Features
Innate Immunity Adaptive Immunity
Germline-encoded receptors Clonally variable receptors generated
targeting pathogen somatically by rearrangement of
molecular patterns gene elements
Does not require immunization Consequence of B- and/or T-cell
activation
Limited memory Immunologic memory well
developed
Includes physical barriers to Antibody and cytotoxic T cells
pathogen
Common Features
Cytokines and chemokines
Complement cascade
Phagocytic cells
Natural killer (NK) cells
“Natural” antibodies
RNA; and bacterial and viral unmethylated CpG DNA. CLRs
are particularly important in antifungal innate immunity but
also have important roles in defenses against bacteria, viruses,
and parasites. They comprise a large family that commonly rec-
ognizes microbe-specific carbohydrate ligands or structurally
similar lectin-like domains. Cytoplasmic PRRs include RIG-1–
like receptors (RLRs) and nucleotide oligomerization domain
(NOD)-like receptors (NLRs). RLRs are involved in recogni-
tion of viruses through interaction with intracytoplasmic viral
double-stranded RNA (dsRNA), and NLRs recognize bacterial
peptidoglycan motifs.4
Cells of the innate immune system are commonly triggered
through activation of the nuclear factor-κB (NF-κB) transcrip-
tion factor via the MyD88 signaling pathway, thereby inducing
an inflammatory response using mechanisms that are broadly
shared with those of the adaptive immune system. These include
activation of various types of ILCs (e.g., natural killer [NK] cells
[Chapter 12]), which are characterized by absence of clonally
expressed receptors for specific antigen (see later), activation of
granulocytes and other phagocytes (Chapter 39), the secretion
of inflammatory cytokines and chemokines, and interactions of
the many participants in the complement cascade (Chapter 40).
In addition, activation of cells of innate immunity that also act
as APCs for the adaptive immune system results in upregulation
of membrane molecules such as CD80 and CD86 (among oth-
ers) that provide the second signal, which along with the T-cell
receptor (TCR) for antigen (Chapter 4), can activate antigen-
specific T cells (Chapter 10).5
Finally, because recognition of pathogens by the innate im-
mune system relies on germline encoded, non-rearranged re-
ceptors held in common by the specific cell type, innate im-
munity is more rapidly responsive. It can initiate in minutes to
hours and generally precedes development of a primary adap-
tive immune response by at least several days.
CELLS OF THE IMMUNE SYSTEM
The major cellular constituents of both innate and adaptive immu-
nity originate in bone marrow, where they differentiate from mul-
tipotent hematopoietic stem cells (HSCs) along several pathways
to become granulocytes, lymphocytes, and APCs (Chapter 2).
3
Granulocytes
Polymorphonuclear leukocytes (granulocytes) are classified by
light microscopy into four types. By far the most abundant in
the peripheral circulation are neutrophils, which are principal
effector cells linking the innate and adaptive responses by virtue
of their expression of surface receptors for antibody and com-
plement (Chapter 40). They are phagocytic cells that ingest, kill,
and degrade microbes and other targets of an immune attack
within specialized cytoplasmic vacuoles that contain potent an-
timicrobial enzymes and oxidative pathways. The phagocytic
activity of neutrophils is promoted by their surface display of
receptors for antibody molecules (specifically the Fc portion of
immunoglobulin G [IgG] molecules) (Chapter 8) and activated
complement proteins (particularly the C3b component) (Chap-
ter 40). Neutrophils are the predominant cell type in acute in-
flammatory infiltrates and are the primary effector cells in im-
mune responses to pyogenic bacteria (Chapter 27).
Eosinophils (Chapter 45) and basophils (Chapter 44) are the
other circulating forms of granulocytes. A close relative of the
basophil, but derived from distinct bone marrow precursors, is
the tissue mast cell, which does not circulate in blood. Eosino-
phils, basophils, and mast cells are important in defenses against
multicellular pathogens, particularly helminths (Chapter 30).
Their defensive functions are not based on phagocytic capabili-
ties but on their ability to discharge potent biologic mediators
from their storage granules into the cellular microenvironment.
This process, termed degranulation, can be triggered by antigen-
specific IgE molecules that bind to basophils and mast cells via
high-affinity receptors for the Fc portion of IgE (FcεR) on their
surfaces. In addition to providing a mechanism for anthelmintic
host defenses and certain antibacterial responses, this is also the
principal mechanism involved in acute (IgE-mediated) allergic
reactions (Chapters 43–50).
Lymphocytes
Three broad categories of lymphocytes are identified on the ba-
sis of display of particular surface molecules: B cells, T cells, and
ILCs. Each of these categories can be further subdivided accord-
ing to specific function and display of distinguishing cell surface
molecules (Chapter 2). All lymphocytes differentiate from com-
mon lymphoid stem cells in bone marrow. B cells create their
Ig receptors in bone marrow and differentiate into antibody-
producing cells in the periphery (Chapter 7). T-cell precursors
move from bone marrow to the thymus (or, in some cases, to
extrathymic tissue compartments), where they complete their
differentiation and selection (Chapter 9).
T cells and B cells are the heart of immune recognition, a
property reflecting their clonally specific cell surface receptors
for antigen (Chapter 4). The TCR is a heterodimeric integral
membrane molecule expressed exclusively by T lymphocytes.
B-cell receptors (BCRs) for antigen are membrane immuno-
globulin (mIg) molecules of the same antigenic specificity that
the B cell and its terminally differentiated progeny, plasma cells,
will secrete as soluble antibodies. Memory B cells and nondivid-
ing, long-lived plasma cells may account substantially for per-
sistence of antibody responses (including production of autoan-
tibodies) over many years.6
Receptors for “antigen” on the third class of lymphocytes,
ILCs, are not clonally expressed. ILCs are subdivided into three
major groups according to the cytokines that they produce. For
example, group 1 ILCs, including NK cells, produce interferon-γ
(IFN-γ) and tumor necrosis factor (TNF).7 ILCs express receptors
4 PART I Principles of Immune Response
for PAMPs and, as such, serve as major effectors of innate immu-
nity. They also recognize target cells that might otherwise elude
the immune system (Chapters 2 and 12). Thus recognition of NK
cell targets is based substantially on what their targets lack rather
than on what they express.
NK cells express receptors of several types for major histo-
compatibility complex (MHC) class I molecules via killer im-
munoglobulin-like receptors (KIRs).8 KIRs are expressed on the
plasma membrane of NK cells (and some T cells), which interact
with class I molecules to alter NK-cell cytotoxic function. Most
KIRs express in their intracellular domain a tyrosine-based in-
hibitory motif (ITIM) that suppresses NK activity, thereby pre-
venting NK cell activity directed against normal self-cells. In
contrast, some KIRs express a tyrosine-based activation motif
(ITAM), which amplifies their activity. NK cells will kill target
cells unless they receive an inhibitory signal transmitted by an
ITIM receptor. Virus-infected cells and tumor cells that attempt
to escape T-cell recognition by downregulating their expression
of class I molecules become susceptible to NK cell–mediated
killing because the NK cells receive an activation signal and/
or fail to receive an inhibitory signal through the ITAM- and
ITIM-containing MHC class I receptors. The balance between
ITIM and ITAM is regulated by the microenvironmental mi-
lieu, increasing expression of ITAM in the presence of virus-
infected or cancer cells and of ITIM as necessary to maintain
self-tolerance and prevent autoimmunity. A high frequency of
ITAM-expressing cells has been reported in some patients with
autoimmune diseases.9
Although NK cell–mediated innate immunity has been long
considered to lack immunologic memory, studies suggest that
NK cells can exhibit memory of previous encounters with mi-
crobes or other antigens, the molecular basis of which remains
to be fully elucidated.10 NK cells can also participate in antigen-
specific immune responses by virtue of their surface display of
the activating ITAM receptor CD16, which binds the constant
(Fc) region of IgG molecules. This enables them to function as
effectors of a cytolytic process termed antibody-dependent cellu-
lar cytotoxicity (ADCC), a mechanism exploited clinically with
monoclonal antibody (mAb) therapeutic agents.11
In general, pathways leading to differentiation of T cells, B
cells, and ILCs are mutually exclusive, representing a permanent
lineage commitment. No lymphocytes express both mIg and
TCRs. However, a subset of T cells, termed NKT cells, exhibit
both NK-like cytotoxicity and αβ TCR with limited receptor
diversity.
Antigen-Presenting Cells
KEY CONCEPTS
Features of Antigen-Presenting Cells
• Capacity for uptake and partial degradation of protein antigens
• Expression of major histocompatibility complex (MHC) molecules for
binding antigenic peptides
• Chemokine receptors to allow colocalization with T cells
• Expression of accessory molecules for interaction with T cells
• Receptors for pathogen- or danger-associated molecular patterns
• Secretion of cytokines that program T helper (Th) cell responses
A morphologically and functionally diverse group of cells, all
of which are derived from bone marrow precursors, is specialized
for presentation of antigen to lymphocytes, particularly T cells
(Chapter 6). Included among such cells are dendritic cells (DCs),
monocytes (present in the peripheral circulation), macrophages
(solid tissue derivatives of monocytes), cutaneous Langerhans
cells (Chapter 23), and constituents of the reticular endothelial
system within solid organs. B lymphocytes that specifically cap-
ture antigen via their clonally expressed mIg can also function
efficiently in antigen presentation to T cells.
Cardinal features of APCs include their expression of both
class I and class II MHC (Chapter 5) molecules as well as requi-
site accessory molecules for T-cell activation (e.g., B7-1, B7-2/
CD80, CD86). Upon activation, APC elaborate cytokines that
induce specific responses in cells to which they are presenting
antigen. In addition to processing and presenting antigen, APCs
can regulate activation of the immune system via innate cell sur-
face receptors, which contribute to determination of whether
the antigen is pathogen associated.
APCs differ substantially among themselves with respect to
mechanisms of antigen uptake and effector functions. Imma-
ture DCs show high phagocytic and pathogen-killing activity
but low ability to present antigen and activate T cells. DCs that
have ingested a pathogen or foreign antigen can be induced to
mature by inflammatory stimuli,12,13 especially via cells of the
innate immune system and by direct activation through recep-
tors for PAMPs or DAMPs. Monocytes and macrophages are
actively phagocytic, particularly for antibody and/or comple-
ment-coated (opsonized) antigens that bind to their surface re-
ceptors for IgG and C3b. These cells are also important effectors
of immune responses, especially in sites of chronic inflamma-
tion. Upon further activation by T-cell cytokines, they can kill
ingested microorganisms by oxidative pathways similar to those
used by polymorphonuclear leukocytes.
The interaction between B cells acting as APCs and T lympho-
cytes is notable because the cells are involved in a mutually ampli-
fying circuitry of antigen presentation and response. The process
is initiated by antigen capture through B-cell mIg and ingestion
by receptor-mediated endocytosis. This is followed by proteolytic
antigen degradation and then display to T cells as oligopeptides
bound to MHC molecules. Like other APCs, B cells display CD80
and thus provide a requisite second signal to the antigen-respon-
sive T cell via CD28, its accessory molecule for activation (Fig. 1.1;
Chapters 4 and 10). As a result of T-cell activation, T-cell cyto-
kines that regulate B-cell differentiation and antibody production
are produced. T cells are stimulated to display the surface ligand
CD40L (CD154), which can serve as the second signal for B-cell
activation through its inducible surface receptor.
BASIS OF ADAPTIVE IMMUNITY
The essence of adaptive immunity is molecular distinction be-
tween self constituents and potential pathogens. For simplic-
ity, this is typically summarized as self/nonself discrimination.
However, more precisely the issue is one of discrimination be-
tween molecular species that are perceived as signaling poten-
tial “danger” versus those that are not. This discrimination is
a major responsibility of both T cells, B cells, and cells of the
innate immune system. This process is more complicated for
T cells because it reflects the selection of thymocytes that have
generated specific antigen receptors that can bind to self-anti-
gens below a certain threshold of activation and then, upon later
encounter, can bind nonself antigenic peptides bound to self-
MHC molecules and be activated to engage in effector function.
 CHAPTER 1 The Human Immune Response 5

VH VH

VL Cµ Cµ VL

CL CL
Cµ Cµ

Cµ Cµ Vα Vβ α1 α2 α1 β1

Cµ Cµ Cα Cβ β2m α3 α2 β2

Cell membrane
migM αβTCR HLA HLA
class I class II
FIG. 1.1 Antigen-Binding Molecules. Antigen-binding pockets of immunoglobulin (Ig) and T-cell receptor (TCR) comprise variable (V)
segments of two chains translated from transcripts that represent rearranged V(D)J or VJ gene elements. Thin red bars designate two
of the complementarity determining regions (CDRs) that form portions of the Ig antigen-binding site. The red ovals with thick red bars
designate the regions of very high sequence variability in both Igs and TCRs that are generated by recombination of the 3′-end of the
V gene element with the D and J gene elements or with the J gene element. In the Ig molecule this is designated CDR3. Antigen-
binding pockets of Ig molecules are formed by the three-dimensional folding of the heavy and light chains that juxtapose the CDRs of
one heavy chain and one light chain. Antigen-binding grooves of MHC molecules are formed with contributions from α1 and β1 domains
of class II molecules and from α1 and α2 domains of class I molecules. All of these molecules are members of the immunoglobulin su-
perfamily. β2m, β2-Microglobulin; C, constant-region domain; HLA, human leukocyte antigen; MHC, major histocompatibility complex;
mIgM, membrane immunoglobulin M.

More subtly, the consequence of this selection process is that for-
eign proteins are recognized as antigens in terms of their ability
to initiate an active immune response, whereas self-proteins are
tolerated (i.e., are not perceived as antigens). B cells that express
self-reactive antibodies are subjected to negative selection in the
bone marrow and the periphery. Through PAMPs/DAMPs and
other, still undefined, mechanisms, the cells of innate immunity
contribute to the essential distinction between commensal (not
dangerous) and potentially pathogenic (dangerous) microbes.
T lymphocytes generally recognize antigens as a complex
of short linear peptides bound to self-MHC molecules on the
surfaces of APCs (Chapter 6). The source of these peptides can
be either extracellular or intracellular proteins, and they can be
derived from either self or foreign (e.g., microbial) molecules.
With the exception of superantigens (SAgs; see later), T cells
neither bind antigen in native conformation nor recognize free
antigen in solution. The vast majority of antigens for T cells are
oligopeptides. However, the antigen receptors of NKT cells can
recognize lipid and glycolipid antigens that are presented to
them by MHC-like CD1 molecules.14
Antigen recognition by T cells differs fundamentally from that
by antibodies, which are produced by B lymphocytes and their de-
rivatives. Antibodies are oriented toward recognition of extracel-
lular threats and, unlike T cells, can bind complex macromolecules
in their native conformation at cell surfaces or in solution. More-
over, antibodies show less preference for recognition of proteins;
antibodies against carbohydrates, nucleic acids, lipids, and simple
chemical moieties can be readily produced. Although B cells can
also be rendered unresponsive by exposure to self-antigens, par-
ticularly during differentiation in bone marrow, this process does
not define foreignness within the context of self-MHC recognition.
Clonal Basis of Immunologic Memory
An essential element of self/nonself discrimination is the clonal
nature of antigen recognition. Although the immune system can
recognize a vast array of distinct antigens, all of the receptors of
a single T cell or B cell (and their clonal progeny) have identical
antigen-binding sites and hence a particular specificity (Chapter 4).
A direct consequence is the capacity for antigen-driven immuno-
logic memory. This phenomenon derives from the fact that, after
an initial encounter with antigen, clones of lymphocytes that can
recognize the antigen proliferate and differentiate into effector cells.
After interaction with their target, most of these effector cells are
consumed or undergo programed cell death. However, a smaller
population of long-lived memory cells persists. These memory cells
constitute a pool of cells larger than the initial naïve responders.
They can elicit a greater and more rapid response upon subsequent
antigen encounter. These two hallmarks of adaptive immunity,
clonal specificity and immunologic memory, provide a conceptual
foundation for the use of vaccines in prevention of infectious dis-
eases (Chapter 87).
Immunologic memory involves not only the T cells charged
with antigen recognition but also the T cells and B cells that
mediate the efferent limb of an inflammatory response. In its at-
tack on foreign targets, the immune system can exhibit exquisite
specificity for the inducing antigen, as is seen in the epitope-
specific lysis of virus-infected target cells by cytolytic T cells.
ANTIGEN-BINDING MOLECULES
KEY CONCEPTS
Features of the Immunoglobulin (Ig) Superfamily
• Large family of ancestrally related genes (more than 100 members)
• Most products involved in immune system function or other cell-cell
interactions
• Ig superfamily members have one or more domains of ∼100 amino
acids, each usually translated from a single exon
• Each Ig domain consists of a pair of β-pleated sheets usually held
together by an intrachain disulfide bond
6 PART I Principles of Immune Response
Three sets of molecules are responsible for the specificity of
adaptive immune responses by virtue of their capacity to bind
foreign antigen. These are Igs, TCRs, and MHC molecules (see
Fig. 1.1; Chapters 4 and 5). All are products of a very large family
of ancestrally related genes, the Ig superfamily, which includes
many other molecules essential to induction and regulation of
immune responses.15,16 Members of the Ig superfamily exhibit
characteristic structural features. The most notable of these is
organization into homologous domains of approximately 110
amino acids that are usually encoded by a single exon with an
intradomain disulfide bond. These domains are characteristi-
cally configured as antiparallel strands, forming two opposing
β-pleated sheets.
Immunoglobulins and T-Cell Receptors
The remarkable specificity of Ig and TCR molecules for an-
tigen is achieved by a mechanism of genetic recombination
that is unique to Ig and TCR genes (Chapter 4). The antigen-
binding site of both types of molecules lies at the tip of the
two juxtaposed, constituent polypeptides and contains con-
tributions from each of the two. In the case of Igs, these are a
heavy (H) chain and one of two alternative types of light (L)
chains, κ or λ. In the case of TCRs, either of two alternative
heterodimers can constitute the antigen-binding molecule,
one composed of α and β chains, and the other of λ and δ
chains. In the case of the TCR, this antigen-binding site is rel-
atively flat, permitting association between the TCR and the
MHC:peptide complex. In the case of Ig, the antigen-binding
site can be concave, flat, or form a projection. This permits the
Ig to bind to a variety of surface structures, including projec-
tions and nooks and crannies.
The polypeptides contributing to both Igs and TCRs can
be divided into an antigen-binding amino-terminal variable
(V) domain and one or more carboxy-terminal constant (i.e.,
nonvariable) domains. Ig constant region domains generally in-
clude specific sites responsible for the biologic effector functions
of the antibody molecule (Chapter 8).
KEY CONCEPTS
Comparison of T- and B-Cell Receptors for Antigen
Similarities
• Members of the immunoglobulin (Ig) superfamily
• Each chain divided into variable and constant regions
• Variable regions constructed by V(D)J rearrangements
• Nongenomic N-nucleotide additions at V(D)J junctions
• Both polypeptide chains contribute to the antigen-binding site
• Exhibit allelic exclusion
• Negative selection against receptors with self-antigen specificity
• Transmembrane signaling involving coreceptor molecules
Differences
• Ig can be secreted; T-cell receptor (TCR) is not
• Ig recognizes conformational antigen (Ag) determinants; TCR recog-
nizes linear determinants
• Ig can bind antigen in solution; TCR binds antigen when presented by
a major histocompatibility complex (MHC) molecule on an antigen-
presenting cell (APC)
• TCRs are positively selected for self-MHC recognition
• Somatic hypermutation of Ig genes can enhance antigen-binding af-
finity
• Ig genes can undergo isotype switching
• Ig constant domains express inflammatory effector functions
The most noteworthy feature of the jawed vertebrate immune
system is the process of recombination-activating gene (RAG)
mediated genetic recombination that generates a virtually lim-
itless array of specific antigen receptors from a rather limited
genomic investment. This phenomenon is accomplished by the
recombination of genomic segments that encode the variable
domains of Ig and TCR polypeptides (Chapter 4).17 The prod-
ucts of these rearranged gene elements provide a specific B or
T cell with its unique antigen receptor. The variable domain of
the mature receptor is created by the rearrangement of two or
three separate gene segments. These are designated V (variable)
and J (joining), for IgL chains and TCR α and γ chains, and V,
D (diversity) and J, for IgH and TCR β and δ chains. In addition
to rearrangement, N-nucleotide addition also contributes sub-
stantially to receptor diversity. N-nucleotide addition results in
the insertion, at the time of rearrangement, of one or more non-
genomic nucleotides at the junctions between V, D, and J seg-
ments through the action of terminal deoxynucleotidyl trans-
ferase (TdT).17 This permits receptor diversity to extend beyond
germline constraints. Analysis of the linear sequences of many
Ig V region domains has shown that they contain three sites of
high sequence variability that have been designated complemen-
tarity determining regions 1–3 (CDR1–3) to indicate that they
are the sites that contact antigen (see Fig. 1.1).
DNA rearrangement involved in generating TCRs and BCRs
is controlled by recombinases that are active in early thymo-
cytes and in B precursor cells in bone marrow. The process is
sequential and carefully regulated, generally leading to transla-
tion of one receptor of unique specificity for any given T or B
lymphocyte. This result is achieved through a process termed
allelic exclusion, wherein only one member of a pair of allelic
genes potentially contributing to an Ig or TCR molecule is rear-
ranged at a time.18
The process of allelic exclusion is not absolute, and a small
number of lymphocytes will express dual functional Ig or TCR
transcripts and, in some cases, two distinct surface receptors.
However, B cells exclusively rearrange Ig genes, not TCR genes,
and vice-versa for T cells. Moreover, after producing a func-
tional heavy chain, B cells sequentially rearrange L chain genes,
typically κ before λ. Thus, in normal individuals, the vast major-
ity of B cells express either κ or λ chains, with 1% or less express-
ing both. Similarly, thymocytes express α and β genes, or γ and
δ genes.
There is one feature of V region construction that is essential-
ly reserved to B cells. This is somatic hypermutation (SHM), a
process that can continue at discrete times throughout the life of
a mature B cell at both the VHDHJH and VLJL gene exons.19,20 Be-
cause these rearranged gene exons encode the antigen-binding
site that contains the specific points of contact with antigen, on
occasion the random process of SHM will result in cells express-
ing mIg with increased affinity for the antigen they recognize.
Typically, cells with increased affinity for antigen are activated
preferentially, particularly at limiting doses of antigen. Thus the
average affinity of antibodies produced during the course of an
immune response tends to increase, a process termed affinity
maturation.
TCRs do not show evidence of SHM. This absence may be re-
lated to the focus on selection in the thymus involving corecog-
nition of a self-MHC molecule and self-peptides,21 (Chapter 9)
rather than the continuous process of antigen-driven selection
in the periphery by B cells after SHM. Thymic selection results
in deletion by apoptosis of the vast majority of differentiating
 CHAPTER 1 The Human Immune Response 7

thymocytes by mechanisms that place stringent boundaries
around the viability of a thymocyte with a newly expressed TCR
specificity. Once a T cell is fully mature and ready for emigration
from the thymus, its TCR is essentially fixed, reducing the likeli-
hood of emergent autoimmune T-cell clones in the periphery.
Receptor Selection
The receptor expressed by a developing thymocyte must be ca-
pable of binding with low-level affinity to some particular MHC
self-molecule, either class I or II, expressed by a resident thymic
epithelial cell or APC. Because their receptors are generated by
a process of semirandom joining of rearranging exon segments
coupled with N-nucleotide additions, most thymocytes fail this
test. They are consequently deleted as not being useful to an im-
mune system that requires T cells to recognize antigen that is
bound to self-MHC molecules. Thymocytes surviving this hur-
dle are said to have been “positively selected” (Fig. 1.2A).21 Con-
versely, a small number of thymocytes bind with an unallowably
high affinity for a combination of MHC molecule plus antigenic
peptide expressed by a thymic APC. Because the peptides avail-
able for MHC binding at this site are derived almost entirely
from self-proteins, differentiating thymocytes with such re-
ceptors are intrinsically dangerous as potentially autoimmune.
This deletion of thymocytes with high-affinity receptors for
self-MHC plus (presumptively) self-peptide is termed “negative
selection” (see Fig. 1.2B),21 a process that may also involve
activity of regulatory T cells (Tregs; Chapter 13).22,23
Another feature that distinguishes B cells from T cells is that
the cell surface antigen receptors of the former can be secreted
in large quantities as antibody molecules, the effector functions
of which are carried out in solution or at the surfaces of other
cells. Secretion is accomplished by alternative splicing of Ig mes-
senger RNAs (mRNAs) to include or exclude a transmembrane
segment that is encoded by the Ig heavy-chain genes.
Immunoglobulin Class Switching
In addition to synthesizing both membrane and secreted forms
of Igs, B cells also undergo class switching. Antibody molecules
are composed of five major classes (isotypes). In order of abun-
dance in serum, these are IgG, IgM, IgA, IgD, and IgE (Chapters
4 and 8). In humans the IgG class is further subdivided into
four subclasses and the IgA class into two subclasses. The class
of Ig is determined by the sequence of the constant region of
its heavy chain (CH). The H-chain constant region gene locus
is organized with exons that encode each of the Ig isotypes and
subclasses located downstream (3′) of the variable (VH) genes.
Thus an antibody-producing cell with a successfully rearranged
VHDHJH exon can change the class of antibody molecule that it

Positive selection Negative selection

Cortical Cortical Med. Med.

Epi Epi Epi Epi
APC APC APC APC

MHC MHC MHC MHC

TCR TCR TCR TCR

Thymocyte Thymocyte Thymocyte Thymocyte

Die or Try again Migrate to Die Emigrate

(Vα–Jα) medulla
A B
FIG. 1.2 Two-Stage Selection of Thymocytes Based on Binding Characteristics of Randomly Gen-
erated T-Cell Receptors. (A) Positive selection. “Double-positive” (CD4+, CD8+) thymocytes with T-cell
receptors (TCRs) capable of low avidity binding to some specific self-MHC molecule (either class I or
II) expressed by thymic cortical epithelial cells (Epi) are positively selected. This process may involve
sequential attempts at α gene rearrangement to express an αβ TCR of appropriate self-MHC specificity.
If binding is to a class I molecule, the positively selected thymocyte becomes CD8 single-positive, and
if to a class II molecule, a CD4 single-positive. Thymocytes that are unsuccessful in achieving a receptor
with avidity for either a class I or II self-MHC molecule die by apoptosis. The solid diamond represents a
self-peptide derived from hydrolysis of an autologous protein present in the thymic microenvironment or
synthesized within the thymic epithelium itself. (B) Negative selection. “Single-positive” (CD4+ or CD8+)
thymocytes, positively selected in the thymic cortex, that display TCRs with high avidity for the combina-
tion of self-MHC plus some self (autologous) peptide present in the thymus are negatively selected (i.e.,
die) as potentially “autoimmune.” Those few thymocytes that have survived both positive and negative
selection emigrate to the periphery as mature T cells. APC, Antigen-presenting cell; MHC, major histo-
compatibility complex.
8 PART I Principles of Immune Response
synthesizes by utilization of different CH genes without changing
its unique antibody specificity. This process, termed class switch
recombination, is regulated by cytokines and is accomplished
through the action of activation-induced cytidine deaminase.24
There is no process comparable to class switch recombina-
tion in T cells. The two types of TCRs are products of four in-
dependent sets of V-region and C-region genes. A large major-
ity of peripheral blood T cells express αβ TCRs, with a small
fraction expressing γδ TCRs (usually ≤5% in peripheral blood).
There is a higher representation of γδ T cells in certain tissues,
particularly those lining mucous membranes, where they may
be specialized for recognition of heavily glycosylated peptides
or nonpeptide antigens that are commonly encountered in these
tissue compartments. Thymocytes are committed to the expres-
sion of either αβ or γδ TCR, and their differentiated progeny (T
cells) never change their TCR type in the periphery.
Major Histocompatibility Complex
MHC molecules constitute a third class of antigen-binding mol-
ecules. When an MHC class I molecule was initially crystallized,
an unknown peptide was found in a binding groove formed by
the first two (α1 and α2) domains of the molecule. This binding
groove has since been established as a general feature of MHC
molecules.25 It is now known that the function of MHC mole-
cules is to present antigen to T cells in the form of oligopeptides
that reside within this antigen-binding groove (Chapter 6). The
most important difference between the nature of the binding
groove of MHC molecules and those of Ig and TCR is that the
former does not represent a consequence of gene rearrange-
ment. Rather, all the available MHC molecules in an individual
are encoded in a linked array, which in humans is located on
chromosome 6 and designated the human leukocyte antigen
(HLA) complex.
MHC molecules are of two basic types, class I and class II.
Class I molecules are found on the surface of almost all somatic
cells, whereas cell surface expression of class II genes is restrict-
ed primarily to cells specialized for APC function. Class I mol-
ecules have a single heavy chain that is an integral membrane
protein composed of three external domains (see Fig. 1.1). The
heavy chain is noncovalently associated with β2-microglobulin,
a nonpolymorphic, non–membrane-bound, single-domain Ig
superfamily molecule that is encoded in humans on chromo-
some 15, not linked to the MHC. In contrast, class II MHC
molecules comprise two polypeptide chains, α and β (or A and
B), of approximately equal size, each of which consists of two
external domains connected to a transmembrane region and
cytoplasmic tail. Both chains of class II molecules are anchored
on the cell by a transmembrane domain, and both are encoded
within the MHC. Class I and class II molecules have a high de-
gree of structural homology, and both fold to form a peptide-
binding groove on their exterior face, with contribution from
the α1 and α2 domains for class I molecules and from α1 and β1
domains for class II.
There are three class I loci (HLA-A, -B, and -C) and three
class II subregions (HLA-DR, -DQ, and -DP) that are princi-
pally involved in antigen presentation to T cells (Chapter 5). The
functions of other class I and class II genes within this com-
plex are less clear. Some, at least, appear to be specialized for
binding (presentation) of peptide antigens of restricted type,
source, or function (e.g., HLA-E),26 and others (e.g., HLA-DM
and HLA-DO) appear to be involved in selective antigen pro-
cessing and loading of antigenic peptides into the binding cleft
of the HLA-DR, -DQ, and -DP molecules (Chapter 6).27 In ad-
dition, members of a family of “nonclassic” class Ib molecules,
CD1a–d, which are encoded on chromosome 1 outside the MHC,
are specialized for binding and presentation of lipid and lipid-
conjugate antigens to T cells.14,28
The HLA complex represents an exceedingly polymorphic
set of genes (Chapter 5). Consequently, most individuals are
heterozygous at each major locus. In contrast to TCRs and Igs,
the genes of the MHC are co-dominantly expressed. Thus, at
a minimum, an APC can express six class I molecules and six
class II molecules (the products of the two alternative alleles of
three class I and three class II loci). This number is, in fact, usu-
ally an underestimate, as a consequence of additional complex-
ity in the organization of the class II region.
ANTIGEN PRESENTATION
Because MHC genes do not undergo recombination, the num-
ber of distinct antigen-binding grooves that they can form is
many orders of magnitude less than that for either TCRs or Igs.
Oligopeptides that bind to MHC molecules are the products of
self or foreign proteins. They are derived by hydrolytic cleavage
within APCs and are loaded into MHC molecules before ex-
pression at the cell surface (Chapter 6). Indeed, stability of MHC
molecules at the cell surface requires the presence of a peptide
in the antigen-binding groove; cells mutant for the loading of
peptide fragments into MHC molecules fail to express MHC
molecules on their cell surfaces.29 Because in the absence of in-
fection most hydrolyzed proteins are of self-origin, the binding
groove of most MHC molecules contains a self-peptide.
Class I and class II molecules differ from one another in the
length of peptides that they bind, usually 8 to 9 amino acids for
class I and 14 to 22 amino acids for class II. Although important
exceptions are clearly demonstrable, they also generally differ
with respect to the source of peptide. Those peptides binding to
class I molecules usually derive from proteins synthesized intra-
cellularly (e.g., autologous proteins, tumor antigens, virus pro-
teins, and proteins from other intracellular microbes), whereas
class II molecules commonly bind peptides derived from pro-
teins synthesized extracellularly (e.g., extracellular bacteria,
nonreplicating vaccines, toxins/allergens). Endogenous pep-
tides are generated by the immunoproteasome and then are
loaded into newly synthesized class I molecules in the endo-
plasmic reticulum following active transport from the cytosol.
In contrast, proteolytic breakdown and loading of exogenous
peptides into class II molecules occurs in acidic endosomal
vacuoles. As a consequence of proteolytic processing and bind-
ing into an MHC molecule, T cells see linear peptide epitopes.
In contrast, because B-cell antigen recognition requires neither
proteolytic processing nor binding into an MHC molecule, B
cells recognize native, three-dimensional epitopes.
In addition to the recognition of lipids and lipid-conjugates
presented by CD1 molecules, there are other exceptions to the
generalization that MHC molecules only present (and T cells
only recognize) oligopeptides. It has been known for many
years that T cells can recognize haptens, presumably covalently
or noncovalently complexed with peptides residing in the anti-
gen-binding groove. This phenomenon is familiar to physicians
as contact dermatitis to nonpeptide antigens, such as urushiol
(from poison ivy) and nickel ion (Chapter 48). In addition, a
newly recognized subset of T cells designated mucosal-asso-
ciated (semi-) invariant T (MAIT) cells recognize vitamin B2
 CHAPTER 1 The Human Immune Response
(riboflavin) and vitamin B9 (folate) derivatives bound to MR1,
a nonpolymorphic MHC class I–like molecule; these vitamin
derivatives are expressed by many strains of bacteria and yeast.
Because MAIT cells constitute approximately 5% of human T
cells and up to 25% of CD8 cells, their binding specificity sug-
gests a role for these cells in host defenses.30 In addition, certain
human γδ T cells can recognize a variety of nonpeptide phos-
phoantigens, such as phosphorylated nucleotides, other phos-
phorylated small molecules, and alkylamines. The role of APCs
and MHC-like molecules in presentation of phosphoantigens to
γδ T cells remains a subject of investigation.
Another exception to the generalization of T-cell recognition
of oligopeptides is represented by a group of proteins termed
superantigens.31 SAgs, of which the staphylococcal enterotoxin
A represents a prototype, are produced by a broad spectrum
of microbes, ranging from retroviruses to bacteria. They differ
from conventional peptide antigens in their mode of contact
both with MHC class II molecules and TCRs (Chapter 6). They
do not undergo processing to oligopeptide fragments. Instead,
they bind as intact proteins to class II molecules and TCRs out-
side the antigen-binding grooves. Their interaction with TCRs
is predominantly determined by variable residues of the TCR
Vβ region. Because SAgs bind more or less independently of the
TCRs α chain and the other variable segments of the β chain,
they are capable of activating much larger numbers of T cells
compared with conventional peptide antigens—hence their
name. SAgs cause a wave of T-cell activation, proliferation, and
production of proinflammatory molecules that can have pro-
found clinical consequences, leading to development of such
diseases as toxic shock syndrome.31
LYMPHOCYTE ADHESION AND TRAFFICKING
The capacity to continuously survey the antigenic environment
is an essential element of immune function. APCs and lym-
phocytes must be able to find antigen wherever it occurs. Sur-
veillance is accomplished through an elaborate interdigitated
circulatory system of blood and lymphatic vessels that establish
connections between the solid organs of the peripheral immune
system (e.g., spleen, lymph nodes, and lymphoid structures in
mucosal tissues) in which the interactions between immune
cells predominantly occur (Chapter 2).
The trafficking and distribution of circulating cells of the
immune system is largely regulated by interactions between
molecules on leukocyte surfaces and ligands on vascular en-
dothelial cells32 (Chapter 16). Leukocyte-specific cellular ad-
hesion molecules can be expressed constitutively or can be
induced by cytokines (e.g., as a consequence of an inflamma-
tory process).
Several families of molecules are involved in the regu-
lation of lymphocyte trafficking. Particularly important
are selectins and integrins, which ensure that mobile cells
home to appropriate locations within lymphoid organs and
other tissues. Selectins are proteins characterized by a dis-
tal carbohydrate-binding (lectin) domain. They bind to
a family of mucin-like molecules, the endothelial vascu-
lar addressins. Integrins are heterodimers essential for the
emigration of leukocytes from blood vessels into tissues.
Members of the selectin and integrin families are involved
in lymphocyte circulation and homing and are also impor-
tant in interactions between APCs, T cells, and B cells in
the induction and expression of immune responses. Certain
9
endothelial adhesion molecules, mostly members of the Ig
superfamily, are similarly involved in promoting interactions
between T cells and APCs, as well as in leukocyte transmigra-
tion from the vasculature. Receptors for chemokines are im-
portant determinants of lymphocyte migration, particularly
in guiding tissue-selective cell trafficking.33
LYMPHOCYTE ACTIVATION
For both B cells and T cells, initial activation is a two-signal event
(Chapters 4 and 10).34 This generalization is particularly true for
immunologically naïve cells that have not been previously ex-
posed to antigen. The first signal is provided by antigen. Most
commonly, antigens for B cells are proteins with distinct sites,
termed epitopes, which are bound by membrane Ig. Such epi-
topes can be linear, defined by a contiguous amino acid sequence
or (more frequently) can be conformationally defined by the
three-dimensional structure of the antigen. Epitopes can also
be simple chemical moieties (haptens) that have been attached,
usually covalently, to amino acid side chains (Chapter 6). In ad-
dition to proteins, some B cells have receptors with specificity
for carbohydrates and, less commonly, lipids or nucleic acids.
Antigens that stimulate B cells can be either in solution or fixed
to a solid matrix (e.g., a cell membrane). As previously noted,
the nature of antigens that stimulate T cells is more limited.
TCRs do not bind antigen in solution but are usually stimulated
only by small molecules, primarily oligopeptides, which reside
within the antigen-binding cleft of a self-MHC molecule.
The second signal requisite for lymphocyte activation is
provided by an accessory molecule expressed on the surface
of the APC (e.g., B7/CD80) for stimulation of T cells or on the
surface of a helper T cell (e.g., CD40L/CD154) for activation
of B lymphocytes. The cell surface receptors for this particular
second signal on T cells is CD28 and on B cells is CD40 (Fig.
1.3). Other cell surface ligand-receptor pairs may similarly
provide the second signal (Chapters 7 and 10). The growth and
differentiation of both T cells and B cells additionally require
stimulation with one or more cytokines, which are peptide
hormones secreted in small quantities by activated leukocytes
and APCs for function in the cellular microenvironment.35 In
the absence of a second signal, cells stimulated only by antigen
become unresponsive to subsequent antigen stimulation (i.e.,
anergic) (Chapter 10).36
Signal transduction through the antigen receptor is a com-
plex process involving interactions between the specific recep-
tor and molecules coexpressed in the cell membrane.37 For B
cells, this is a heterodimer, Igα/Igβ; and for T cells it is a mac-
romolecular complex, CD3, usually comprising γ, δ, ε, and ζ
chains.
Within the cell membrane, antigen receptor stimulation
induces phosphorylation of Igα/Igβ or CD3 and hydrolysis
of phosphatidylinositol 4,5-bisphosphate by phospholipase
C, leading to generation of diacylglycerol (DAG) and inositol
1,4,5-triphosphate (IP3). As a consequence of signal transduc-
tion and secondarily of DAG and IP3 generation, tyrosine and
serine/threonine protein kinases are activated. In turn, these ki-
nases catalyze phosphorylation of a number of signal-transduc-
ing proteins. This leads to activation of cytoplasmic transcrip-
tion factors NF-AT in T cells and NF-κB in both T cells and B
cells. These transcription factors then translocate to the nucleus,
where they bind to 5′ regulatory regions of genes that are critical
to generalized lymphocyte activation (Chapter 10).38
10 PART I Principles of Immune Response
T cell B cell
mIg + Ag
CD40
TCR Class II + peptide
CD28
Up-regulation
mIg + Ag
CD40L CD40
TCR Class II + peptide
CD28 CD80 (B7)
Cytokines
FIG. 1.3 Reciprocal Activation Events Involved in Mutual
Simulation of T and B Cells. T cells constitutively express T-
cell receptors (TCRs) and CD28. B cells constitutively express
mIg and major histocompatibility complex (MHC) class II. An-
tigen bound to mIg is endocytosed and processed to peptide
fragments that bind to MHC class II molecules for presenta-
tion to TCRs. Activation of B cells by antigen (Ag) upregulates
their expression of CD80 that interacts with CD28 to activate T
cells. This upregulates CD40L (CD154) on the T cell and induces
cytokine synthesis. Costimulation of B cells by antigen CD40L
and cytokines leads to Ig production. mIg, Membrane immuno-
globulin.
CELL-MEDIATED IMMUNE RESPONSES
T-Cell Subsets
T lymphocytes expressing an αβ TCR can be divided into two
major subpopulations based on the class of MHC molecule that
their TCR recognizes and the consequent expression of one of a
pair of TCR accessory molecules, CD4 or CD8 (Chapters 4 and
9). Binding of CD4 to class II MHC molecules or CD8 to class
I MHC molecules on APCs contributes to the overall strength
of intercellular molecular interactions. The ratio of CD4 to CD8
cells in peripheral blood is usually approximately 2:1.
CD4 T Cells, Cytokines, and Chemokines
The activities of CD4 T lymphocytes, commonly referred to as
T helper (Th) cells, are mediated predominantly through the se-
cretion of cytokines (Chapter 14). Cytokine activity can include
autostimulation (autocrine function) if the cell producing the
cytokine also expresses a surface receptor for it, or stimulation
of other cells in the microenvironment of the cytokine-secreting
cell (paracrine function) including B cells, APCs, and other T
cells. Although it is now recognized that their biologic effects
are broader than implied by their name, many of the principal
cytokines active in the immune system are known as interleu-
kins (ILs), implying that they are produced by a leukocyte to act
on other leukocytes.
The specific profile of cytokines produced by CD4 T
cells allows further functional subdivision (Chapters 11 and
14).35,39 CD4 T cells elaborating the “inflammatory” cytokines
involved in effector functions of cell-mediated immunity,
such as IL-2 and IFN-γ, are designated Th1 cells. Th2 CD4
T cells synthesize cytokines (Chapter 14), such as IL-4 and
IL-13, which control and regulate antibody responses and ac-
tivate cells that are involved in host defense against parasites.
Differentiation of Th1 versus Th2 subsets is a process substan-
tially controlled by positive feedback loops, being promoted
particularly by IL-12 in the case of Th1 cells and IL-4 in the
case of Th2 cells.
It is important to note that generalizations regarding cytokine
activity are usually oversimplifications, reflecting a substantial
overlap and multiplicity of functions. For example, although
IL-2 was initially identified as a T-cell growth factor, it also sig-
nificantly affects B-cell differentiation. The prototypic inflamma-
tory cytokine, IFN-γ, which promotes differentiation of effector
function of cytotoxic T lymphocytes (CTLs) and macrophages,
is also involved in regulation of Ig isotype switching. Similarly,
IL-4 is known primarily as a B-cell growth and differentiation
factor, but it can also stimulate proliferation of T cells.
A distinct subset of cytokines is a large group of highly con-
served cytokine-like molecules, smaller than typical cytokines
(~7 to 12 kilodaltons [kDa]), termed chemotactic cytokines, or
chemokines (Chapter 15).33 Chemokines are classified on the
basis of the number and spacing of specific cysteine residues.
They regulate and coordinate trafficking and activation of leu-
kocytes, functioning importantly in host defenses, and also
broadly in a variety of nonimmunologic processes, including
organ development and angiogenesis. They are characterized
by binding to seven-transmembrane-domain G protein–cou-
pled receptors. Of particular interest to clinical immunologists
are the chemokine receptors CCR5 and CXCR4. Together with
CD4, these molecules are used as coreceptors by human im-
munodeficiency virus (HIV) to gain entry into target cells
(Chapter 41).40
Cytokines produced by activated T cells can downregulate as
well as initiate or amplify immune responses.41 Downregulating
cytokines include IL-10 (produced by both T cells and B cells)
and transforming growth factor-β (TGF-β). The functions of
IL-10 in vivo are thought to include both suppression of proin-
flammatory cytokine production and enhancement of IgM and
IgA synthesis. TGF-β, which is produced by virtually all cells,
expresses a broad array of biologic activities. These include pro-
motion of wound healing and suppression of both humoral and
cell-mediated immune responses.
In addition to their central role in initiation and regulation of
immune responses, CD4 T cells are important effectors of cell-
mediated immunity (Chapter 11). Through the elaboration of
inflammatory cytokines, particularly IFN-γ, they are essential
contributors to the generation of chronic inflammation, which
is characterized histologically by mononuclear cell infiltrates.
Here their principal role is thought to be the activation of mac-
rophages. In some circumstances, CD4 T cells can function as
cytotoxic effectors, either directly as CTLs, in which case the
killing is “restricted” for recognition of antigen-bound self-
MHC class II, or through the elaboration of cytotoxic cytokines,
such as lymphotoxin and tumor necrosis factor (TNF).
A third subset of Th cells, designated Th17, has been recog-
nized more recently. With differentiation driven particularly by
TGF-β and IL-23 and characterized by the production of the
proinflammatory cytokine IL-17, Th17 cells are important in
the induction and exacerbation of autoimmunity in a variety
of disease models, as well as in host defenses against a broad
 CHAPTER 1 The Human Immune Response
spectrum of extracellular bacteria, fungi, and other pathogens.42
Research continues to identify additional examples of CD4 T
cells that may become recognized as distinct subsets. Their
function is governed by other predominantly expressed cyto-
kines to achieve specialized effector responses.
One final category of CD4 cells, Tregs, plays a crucial role
suppressing the functions of other lymphocytes (Chapter 13).
Tregs can differentiate either in the thymus (tTregs) or in the pe-
riphery (pTregs). A third category of Tregs are induced in vitro
(iTregs).43 Tregs are commonly characterized by surface expres-
sion of CD4 and CD25 and by nuclear expression of the tran-
scription factor Foxp3. Peripheral activation of CD25+ Tregs
is via the TCRs. The cells are IL-2 dependent and apparently
require cell-to-cell contact for suppressive function. They can
suppress functions of both CD4 and CD8 T cells, as well as B
cells, NK cells, and NKT cells. In contrast to activation, sup-
pressor effects are independent of the antigen specificity of the
target cells. Other Tregs are noted for production of inhibitory
cytokines. These include IL-10– and TGF-β–secreting Th3 cells
and IL-10–producing Tr1 cells.44,45
CD8 T Cells
The best understood function of CD8 T cells is that of CTL
effectors.46 CTLs are particularly important in host defenses
against virus-infected cells, where they can kill target cells
expressing viral peptides bound to self-MHC class I mol-
ecules (Chapter 12). This process is highly specific and re-
quires direct apposition of CTLs and target cell membranes.
Bystander cells expressing MHC molecules that have bound
peptides that the CD8 T cell does not recognize are not af-
fected. The killing is unidirectional; the CTL itself is not
harmed and after transmission of a “lethal hit” it can detach
from one target to seek another. Killing occurs via two mech-
anisms: a death receptor–induced apoptotic mechanism and
a mechanism involving insertion of perforins into the target
cell membrane to create a pore through which granzymes
and other cytotoxic enzymes can be transferred from the
CTL into the target cell. CTL activity is enhanced by IFN-γ.
As CTL function is dependent on target cell surface display
of MHC class I molecules, a principal mechanism of immune
evasion by viruses and tumors is elaboration of factors that
downregulate class I expression (Chapter 25). However, this
increases susceptibility of such cells to cytolysis by NK cells
that are activated to attack cells expressing low levels of class
I MHC molecules.
ANTIBODY-MEDIATED IMMUNE RESPONSES
The structure of antibodies permits a virtually limitless binding
specificity of its antigen-binding site. Antigen binding can then
be translated into biologic effector functions based on properties
of the larger nonvariable (constant) region of its heavy chains
(Fc fragment) (Chapter 8). Moreover, in response to cytokines
in the cellular microenvironment, the mechanism of isotype
switching enables the antibody-producing cell to switch the ex-
ons that are used to encode its heavy-chain constant region and
thereby alter the biologic effects of its secreted product without
affecting its antigen-binding specificity. With functional hetero-
geneity determined by isotype, antibody molecules provide a
broad-based and efficient defense system against extracellular
microbes or foreign macromolecules (e.g., toxins and venoms)
(Chapters 8, 27, and 87).
11
KEY CONCEPTS
Biologic Properties of Immunoglobulin (Ig) Classes
• IgM
• Monomeric on the cell surface, primarily pentameric in soluble
form
• Principal Ig of the primary immune response
• Generally restricted to the vascular compartment
• Antigen receptor (monomer) for most naïve B cells
• Fixes complement potently
• IgG
• Monomeric
• Principal Ig of internal secondary immune responses
• Binds to Fcγ receptors on neutrophils, monocytes/macrophages,
and NK cells
• Four subclasses, each with a different effector function
• Fixes complement (except IgG4 subclass)
• IgA
• Monomeric or dimeric
• Transported into the gut
• Principal Ig of mucosal immunity
• Two subclasses
• IgD
• Antigen receptor for mature B cells
• Typically expressed on cells that also express membrane IgM
• IgE
• Binds to Fcε receptors on mast cells and basophils
• Antibody of immediate hypersensitivity
• Important in defenses against helminths
Each antibody class contributes differently to an integrated
defense system.47 IgM is the predominant class formed on initial
contact with antigen (primary immune response). As a mono-
meric structure comprises two light (κ or λ) and two heavy (μ)
chains, it is initially expressed as a membrane-bound antigen
receptor on the surface of B lymphocytes. The avidity of serum
IgM for antigen binding is increased by its organization into a
pentamer of five of the monomeric subunits held together by a
joining (J) chain. IgM is essentially confined to the intravascu-
lar compartment. As a multivalent antigen binder that can effi-
ciently activate (“fix”) complement, it is an important contribu-
tor to immune responses early after the initial encounter with
antigen. The synthesis of IgM, compared with other isotypes, is
much less dependent on the activity of T lymphocytes.
IgG is the most abundant Ig in serum and the principal an-
tibody class of a secondary (anamnestic or memory) immune
response. IgG molecules are heterodimeric monomers with two
light (κ or λ) and two heavy (γ) chains and, except for IgG4,
joined by interchain disulfide bridges. Because of its abundance,
its capacity to fix complement, and the expression on phago-
cytes of Fcγ receptors, IgG is the most important antibody for
systemic secondary immune responses. IgG is the only isotype
that is actively transported across the placenta. These trans-
ported maternal IgG antibodies provide the neonate with an
important level of antibody protection in the first 6 months of
life, when its own antigen-driven antibody responses are first
developing (Chapter 21).
IgA is the principal antibody in the body's secretions (Chap-
ter 24). It is found in serum in monomeric form of two light
and two heavy (α) chains or as a dimer joined by J chain. In
secretions, it is usually present in dimeric form and is actively
secreted across mucous membranes by attachment of a special-
ized secretory component (SC) that is recognized by the polyIg
receptor on mucosal epithelial cells. Dimeric IgA is found in
12 PART I Principles of Immune Response
high concentration in tears, saliva, and secretions of the respira-
tory, gastrointestinal, and genitourinary systems. It is relatively
resistant to enzymatic digestion. It is particularly abundant
in colostrum, where its concentration may be greater than 50
times that in serum, providing passive immunity to the gastro-
intestinal system of a nursing neonate. IgA does not fix comple-
ment by the antibody-dependent pathway and hence does not
promote phagocytosis. Its role in host defenses lies in prevent-
ing a breach of the mucous membrane surface by microbes or
their toxic products.
IgD and IgE are present in serum at concentrations much
lower than that of IgG. The biologic role of serum IgD remains
controversial.48 B cells can express both membrane IgM and IgD
by alternative splicing of the Ig heavy-chain gene or can secrete
only IgD via an apparently atypical form of class switch recom-
bination. These mechanisms do not require T-cell help.
Although IgE is the least abundant isotype in serum, it has
dramatic biologic effects because it is responsible for immediate-
type hypersensitivity reactions, including systemic anaphylaxis
(Chapter 46). Such reactions reflect expression of high-affinity
receptors for Fcε on the surfaces of mast cells and basophils.
Cross-linking of IgE molecules on such cells by antigen induces
their degranulation, with the immediate release of preformed
potent biologic mediators and de novo synthesis and secretion
of additional proinflammatory molecules. The protective role of
IgE is in host defenses against parasitic infestation, particularly
with helminths (Chapter 30).
Complement and Immune Complexes
The effector functions of IgG and IgM depend, in part, on their
capacities to activate the complement system. Through a cascade
of sequential substrate-enzyme interactions, the 11 principal
components of the antibody-dependent complement cascade
(C1q, C1r, C1s, and C2–C9) cause many of the principal conse-
quences of an antigen-antibody interaction (Chapter 40). These
include the establishment of pores in a target cell membrane by
the terminal components (C5–C9) leading to osmotic lysis; the
production of factors (principally C5a) with chemotactic activi-
ty for phagocytic myeloid cells; opsonization by C3b, promoting
phagocytosis; and the ability to induce degranulation of mast
cells (C3a, C4a, and C5a).
There are three distinct pathways to complement activa-
tion.49 The pathway mediated by the binding of the first com-
ponent (specifically C1q) to IgG or IgM has been termed the
“classical” pathway (CP). The lectin pathway is similar to the
CP but is activated by selected carbohydrate-binding proteins,
the mannose (or mannan)-binding lectin (MBL), and ficolins,
which recognize certain carbohydrate repeating structures on
microorganisms. MBL and ficolins are plasma proteins that are
homologous to C1q and contribute to innate immunity through
their capacity to induce antibody- and C1q-independent activa-
tion of the CP. Finally, a large number of substances, including
certain bacterial, fungal, and viral products, can directly activate
the cascade through a distinct series of proteins also leading to
activation of the central C3 component. Although bypassing
C1, C4, and C2, this distinct pathway can achieve all the biolog-
ic consequences of C3 to C9 activation. Non–antibody-induced
activation of C3 is referred to as the “alternative” pathway (AP)
or “properdin” pathway. In addition, the central components of
the cascade (e.g., C5a) can be directly produced by the action
of serine proteases of the coagulation system.49 Reflecting these
separate pathways to activation and the fact that many types of
leukocytes express receptors for activated complement compo-
nents, the complement system is a major contributor to the ef-
ferent limbs of both innate and adaptive immune systems.
In addition to their roles in pathogen/antigen elimination,
constituents of the complement system, together with antigen-
antibody (immune) complexes, act at leukocyte surfaces to reg-
ulate immune functions. For example, interaction of immune
complexes via FcγR on B cells decreases their responsiveness to
stimulation. In contrast, complement activation on B-cell sur-
faces co-ligates their receptors with BCRs for antigen, rendering
the cells more readily activated and resistant to apoptosis.
Essential for the proper function of the complement system
is a series of downregulatory mechanisms that prevent unwant-
ed activation of the system and that extinguish its activity when
no longer needed. The regulatory pathways are mediated by a
combination of both soluble complement-binding and digest-
ing molecules and cell surface binding proteins.
APOPTOSIS AND IMMUNE HOMEOSTASIS
An immune response is commonly first viewed in a “positive”
sense—that is, lymphocytes are activated, proliferate, differenti-
ate, and carry out effector functions. However, it is equally im-
portant that this positive response be tightly regulated by mech-
anisms that operate to turn off the response and to eliminate
cells no longer required (Chapter 17).50,51 Under physiologic
circumstances, once an immune response fades, commonly as
a consequence of antigen depletion, two pathways to terminal
lymphocyte differentiation become available: apoptosis or dif-
ferentiation into memory cells. Memory cells are, of course, a
key to the effectiveness of the adaptive immune system, because
a second activating encounter with antigen (e.g., pathogen) is
both more rapid and more productive. Isotype-switched high-
affinity antibodies are rapidly produced, and/or clones of CTL
effector cells proliferate. However, the majority of lymphocytes
in an active response are not required for maintenance of im-
munologic memory, and the necessity for homeostasis leads to
apoptosis of cells no longer required.
Apoptosis (or regulated cell death [RCD]) is a unique process
of cellular death and widely conserved phylogenetically. It is dis-
tinguished from death by necrosis by cellular shrinking, DNA
fragmentation, and breakdown of cells into “apoptotic bodies”
containing nuclear fragments and intact organelles that can be
eliminated by phagocytosis without release into the extracel-
lular space of the majority of intracellular, especially nuclear,
components. Necrosis can be genetically determined (regulated
necrosis [RN]) or unregulated, reflecting some accidental or
otherwise inevitable process. Apoptosis depends on the activa-
tion of cysteinyl proteases, termed caspases, which cleave pro-
teins that regulate DNA repair and the establishment/mainte-
nance of cellular architecture. In the absence of these apoptotic
mechanisms, massive proliferation of cells in lymphoid tissues
results. This is seen clinically as autoimmune lymphoprolifera-
tive syndrome (ALPS), which is characterized by lymphocytosis
with lymphadenopathy and splenomegaly as well as autoimmu-
nity and hypergammaglobulinemia (Chapter 51).52
MECHANISMS OF IMMUNOLOGIC DISEASES
Immunologic diseases can be classified on the basis of our un-
derstanding of normal immune physiology and its perturba-
tions in disease states (Table 1.2). One type of immunologic
 CHAPTER 1 The Human Immune Response
TABLE 1.2 Mechanisms of Immunologic
Diseases
1. Functional deficiency of key immune system components
a. Congenital
b. Acquired
2. Malignant transformation of immune system cells
3. Immunologic dysregulation
4. Autoimmunity
5. Untoward consequences of physiologic immune function
disease results from failure or deficiency of a component of the
immune system leading to failure of normal immune function
(Chapters 32–42). Such disorders are usually identified by in-
creased susceptibility to infection (Chapter 32). Failure of host
defense can be congenital (e.g., X-linked agammaglobulinemia;
Chapter 33) or acquired (e.g., acquired immunodeficiency syn-
drome [AIDS]; Chapter 41). It can be global (e.g., severe com-
bined immunodeficiency [SCID]; Chapter 34) or, quite specific,
involving only a single component of the immune system (e.g.,
selective IgA deficiency; Chapter 33).
A second type of immunologic disease is malignant transfor-
mation of immunologic cells (Chapters 77–81). Manifestations
of leukocyte malignancies are protean, most commonly reflect-
ing the secondary consequences of solid organ or bone marrow
infiltration or replacement of normal cells by tumor cells, with
resulting anemia and immunologic deficiency.
The remaining types of immunopathogenesis are more spe-
cific to the immune system. Dysregulation of an essentially in-
tact immune system constitutes a third general type of immune
disorder. Features of an optimal immune response include anti-
gen recognition and elimination, with little adverse effect on the
host. However, both initiation and termination of the response
involve regulatory interactions that can go awry when the host
is challenged by antigens of a particular structure or presented
in a particular fashion. Diseases of immune dysregulation can
result from genetic and environmental factors that act together
to produce a pathologic immune response, such as acute aller-
gic diseases (Chapters 43–50). Some forms of allergic disease
are thought to be a consequence of insufficient exposure to
nonpathogenic microbes and other potential allergens in early
childhood, resulting in an increased susceptibility to allergy,
atopy, and asthma once the immune system has matured. The
so-called hygiene hypothesis suggests that mucosal tissue–colo-
nizing organisms play key roles in the initial establishment of
immune homeostasis.53 The importance of establishing immune
homeostasis early in life is also supported by studies demon-
strating reduction in the likelihood of food allergy associated
with feeding of the allergenic foods to infants at high risk for
allergy (Chapter 49).54–56
A fourth type of immunologic disorder is the result of failure
of a key feature of normal immune recognition, the molecu-
lar discrimination between self and nonself. Ambiguity in this
discrimination can lead to autoimmune tissue damage (Chap-
ters 51–76). Although such damage can be mediated by either
antibodies or T cells, the common association of specific au-
toimmune diseases with inheritance of particular HLA alleles
(Chapter 5) suggests that the pathogenesis of autoimmune dis-
eases usually represents a failure of regulation of the anti-self
inflammatory response by T cells.
13
The immunologic attack on self-tissues can be general,
leading to systemic autoimmunity, such as systemic lupus ery-
thematosus; or it can be localized, as in organ-specific auto-
immune diseases. In the latter instances, the immune system
attacks specific types of cells and usually particular cell surface
molecules. In most cases, pathology is a consequence of tar-
get tissue destruction (e.g., multiple sclerosis, rheumatoid ar-
thritis, or insulin-dependent diabetes mellitus). However, de-
pending on the antigenic specificity of the abnormal immune
response, autoimmunity can lead to receptor blockade (e.g.,
myasthenia gravis or insulin-resistant diabetes) or hormone
receptor stimulation (e.g., Graves disease). It is thought by
many immunologists that ambiguity in self/nonself discrimi-
nation is commonly triggered by an unresolved encounter
with an infectious organism or other environmental agent that
shares some structural features with self-tissue structures, al-
though this remains a subject of controversy (Chapter 51).57,58
Insight into mechanisms whereby specific HLA alleles pre-
dispose to development of autoimmunity and others may be
protective are suggested by studies in HLA-transgenic mice,
which suggest that alleles that predispose animals to a particu-
lar autoimmune disease may reflect a T-cell phenotype associ-
ated with secretion of proinflammatory cytokines. In contrast,
protective alleles were associated with elaboration of tolero-
genic cytokines by Tregs.59
A fifth form of immunologic disease occurs as a result of
physiologic, rather than pathologic, immune functions. Inflam-
matory lesions in such diseases are the result of the normal
function of the immune system. A typical example is contact
dermatitis to such potent skin sensitizers as urushiol, the caus-
ative agent of poison ivy dermatitis (Chapter 48). These diseases
can also have an iatrogenic etiology that can range from mild
and self-limited (e.g., delayed hypersensitivity skin test reac-
tions) to life threatening (e.g., graft-versus-host disease, organ
graft rejection).
HOST IMMUNE DEFENSES SUMMARIZED
The first response upon initial contact with an invading patho-
gen depends on components of the innate immune system
(Chapter 3). This response begins with recognition of PAMPs
expressed by cells of the pathogen. These include lipoproteins,
lipopolysaccharide, unmethylated CpG-DNA, and bacterial
flagellin, among others. PAMPs bind to PRRs on or within ef-
fector cells of the host's innate immune system, including DCs,
granulocytes, and ILCs.2,3 The best characterized PRRs are the
TLRs, first recognized as determinants of embryonic patterning
in Drosophila and subsequently appreciated as components of
host defenses in both insects and vertebrates. TLR subfamilies
can be distinguished by expression either on the cell surface or
in intracellular compartments. A second major family of PRRs
comprises NLRs, which detect intracellular microbial products.
Binding of TLRs or NLRs by PAMP ligands triggers intracellu-
lar signaling pathways via multiple “adapters,” leading to a vig-
orous inflammatory response.
The innate immune response also includes the capacity of
NK lymphocytes to identify and destroy, by direct cytotoxic
mechanisms, cells lacking surface expression of MHC class I
molecules, which marks them as potentially pathogenic.4 In ad-
dition, an innate immune response involves elements of the hu-
moral immune system that function independently of antibody,
especially the activation of the complement cascade through
14 PART I Principles of Immune Response

the lectin pathway and the AP, with consequent opsonization

of particles and microbes to promote their phagocytosis and
destruction.
The nature of the adaptive immune response to any partic-
ular pathogenic agent is determined largely by the context in
which the pathogen is encountered. Regardless, effectiveness
depends on the four principal properties of adaptive immuni-
ty: (i) a virtually unlimited capacity to bind macromolecules,
particularly proteins, with exquisite specificity, reflecting gen-
erations of antigen-binding receptors by genetic recombina-
tion and, in the case of B cells, SHM; (ii) the capacity for self/
nonself discrimination, consequences of a rigorous process
involving positive and negative selection during thymocyte
differentiation, as well as negative selection during B-cell
differentiation; (iii) the property of immunologic memory,
reflecting antigen-driven clonal proliferation of T cells and
B cells, which results in increasingly rapid and effective re-
sponses on second and subsequent encounters with a particu-
lar antigen or pathogen; and (iv) mechanisms for pathogen
destruction, including direct cellular cytotoxicity, release of
inflammatory cytokines, opsonization with antibody and
complement, and neutralization in solution by antigen pre-
cipitation or conformational alteration plus phagocytosis and
intracellular digestion.
Although most acquired immune responses include mul- FIG. 1.4 Leg of a 16-year-old patient with chronic mucocu-
tiple defense mechanisms, several generalizations may be con- taneous candidiasis as a consequence of a congenital T-cell
ceptually useful. T cell–mediated (and NK cell–mediated) ef- deficiency associated with hypoparathyroidism and adrenal
fector functions are particularly important in defenses against insufficiency.
pathogens encountered intracellularly or at cell surfaces, such
as intracellular viruses, intracellular bacteria, and tumor cells.
These responses involve the production of inflammatory cyto-
kines by CD4 Th1 cells, as well as the direct cytolytic activity
of CD8 CTLs. In contrast, host defenses to most antigens en- Patients with defects in antibody synthesis or phagocytic cell
countered primarily in the extracellular milieu are largely de- function are characteristically afflicted with recurrent infections
pendent on humoral mechanisms (antibody and complement) with pyogenic bacteria, particularly gram-positive organisms.
for antigen neutralization, precipitation, or opsonization and And patients with inherited defects in synthesis of terminal
subsequent destruction by phagocytes. Targets of antibody- complement components have increased susceptibility to infec-
mediated immunity include extracellular virus particles, tion with species of Neisseria.
bacteria, and toxins (or other foreign proteins). However, it In recent years, immunology has entered the lay lexicon,
is worth reiterating that induction of an effective antibody re- largely as a result of the HIV and Covid-19 pandemics. Peo-
sponse (including isotype switching) and development of im- ple throughout the world are now aware of the tragic con-
munologic memory (resulting from B-cell clonal expansion sequences of immune deficiency. However, the remarkable
and B memory cell differentiation) require antigen activation progress in understanding this diseases rested substantially
not only of specific B cells but also CD4 T cells, particularly on earlier studies of relatively rare patients with primary im-
of the Th2 type. In addition, antibacterial and antifungal re- munodeficiency syndromes and on genomic definition of
sponses that involve prominent responses by neutrophils re- their molecular basis. Similarly, cure of patients with primary
quire CD4 T cells of the Th17 type. immunodeficiencies by cellular reconstitution, particularly
Finally, clinical “experiments of nature” have proven particu- bone marrow or stem cell transplantation (Chapter 90),62 pre-
larly instructive in our efforts to understand the role of specific saged recent progress in correction of such diseases by gene
components of the immune system in overall host defenses replacement therapy (Chapter 91).63 The “present” of clinical
(Chapter 32).60 The importance of T cell–mediated immunity immunology is, indeed, bright, but its future potential to im-
in host defenses to intracellular parasites, fungi (Fig. 1.4), and pact prevention and treatment of many challenging diseases,
viruses is emphasized by the remarkable susceptibility of pa- including cancer (Chapters 80 and 81), through specific anal-
tients with T cell deficiency to pathogenic organisms, such as ysis of genetic mutations and enhancement or suppression of
Pneumocystis jiroveci and Candida albicans, and by the fact that antigen-specific immune responses with chimeric antigen re-
using attenuated live virus vaccines in such patients can lead ceptor (CAR) T cells and checkpoint blockade (CPB) is even
to devastating disseminated infections. Indeed, the relationship more exciting to contemplate.64 A few approaches are broadly
between susceptibility to particular potential pathogens and hinted at here, and it is hoped that readers will enjoy con-
specific immunologic deficiencies is nicely illustrated by dem- sidering such “perspectives” throughout the book. Given the
onstrations that the pathogenesis of various familial forms of nature of the immune system, it is also hoped it will challenge
chronic mucocutaneous candidiasis reflect deficiency of IL-17– readers to transform a particular author's views to new and
mediated immunity.61 different clinical settings.
 CHAPTER 1 The Human Immune Response
ON THE HORIZON
Enhancement of Immune Responses
• Use of CRISPR/Cas9 technology in correction of gene defect in
monogenic immunodeficiency diseases
• Enhancement of molecular pathway–specific cancer immunotherapy
• Prediction of molecular targets and improvements in adjuvants for
vaccines
Suppression of Immune Responses
• Further development of protocols for prevention of childhood allergic
diseases by appropriate environmental exposures in infancy
• Improved allergen-specific immunotherapy of allergic diseases
• Prevention of graft-versus-host disease in allogeneic bone marrow
transplantation cases
• Induction of antigen-specific immune tolerance in humans
• Pharmacologic development of specific inhibitors of cytokines, che-
mokines, and their receptors
Immunodiagnostics and Immunopathogenesis
• Routine use of genomic analysis for development of personalized
medicine applicable to immunologic diseases
• Development of novel diagnostic tools based on nanotechnology ar-
rays
• Application of gastrointestinal microbiome analysis in understanding
the pathogenesis of inflammatory bowel diseases, leading to novel
therapeutic options
• Understanding the role of inflammation in the pathogenesis of lead-
ing causes of morbidity and mortality, including myocardial infarction,
stroke, and Alzheimer disease
Studies in experimental animals, especially murine studies,
have been critical to our understanding of molecular aspects of
immune system function and have contributed importantly to
our appreciation of how aberrations of such functions are in-
volved in the pathogenesis of disease. Insights gained from use of
transgenic mice (including murine expression of human genes)
and constitutive or conditional gene-knockout mice are essential
to a comprehensive view of the immune system at the advancing
edge of its clinical application, implying that future progress in
clinical immunology will equally depend on detailed analysis in
such systems. However, it has become apparent that there are im-
portant differences in aspects of the human and rodent immune
systems. Consequently, the carefully studied patient, particularly
when coupled with the power of increasingly feasible genome and
transcriptome sequencing, will remain the ultimate crucible for
understanding human immunity and the roles of the immune
system in the pathogenesis of and protection from disease.
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Another random document with
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that, if the thief does not restore the stolen property, he will be a
dead man within a month.34.1
Similarly in Nias, an island to the west of
Thieves cursed in Sumatra, when a thief cannot be found he is
Nias.
cursed, and to give weight to the curse a dog is
burned alive. While the animal is expiring in torments, the man who
has been robbed expresses his wish that the thief may likewise die
in agony; and they say that thieves who have been often cursed do
die screaming.34.2 Curses are also employed for
Thieves cursed
among the Sea
the same purpose with excellent effect by the Sea
Dyaks of Borneo. Dyaks of Borneo. On this point a missionary bears
the following testimony. “With an experience of
nearly twenty years in Borneo, during which I came into contact with
thousands of the people, I have known of only two instances of theft
among the Dyaks. One was a theft of rice. The woman who lost the
rice most solemnly and publicly cursed the thief, whoever it might be.
The next night the rice was secretly left at her door. The other was a
theft of money. In this case, too, the thief was cursed. The greater
part of the money was afterwards found returned to the box from
which it had been abstracted. Both these incidents show the great
dread the Dyak has of a curse. Even an undeserved curse is
considered a terrible thing, and, according to Dyak law, to curse a
person for no reason at all is a fineable offence.
“A Dyak curse is a terrible thing to listen to. I have only once heard
a Dyak curse, and I am sure I do not want to do so again. I was
travelling in the Saribas district, and at that time many of the Dyaks
there had gone in for coffee-planting; indeed, several of them had
started coffee plantations on a small scale. A woman told me that
some one had over and over again stolen the ripe coffee-berries
from her plantation. Not only were the ripe berries stolen, but the
thief had carelessly picked many of the young berries and thrown
them on the ground, and many of the branches of the plants had
been broken off. In the evening, when I was seated in the public part
of the house with many Dyak men and women round me, we
happened to talk about coffee-planting. The woman was present,
and told us of her experiences, and how her coffee had been stolen
by some thief, who, she thought, must be one of the inmates of the
house. Then she solemnly cursed the thief. She began in a calm
voice, but worked herself up into a frenzy. We all listened horror-
struck, and no one interrupted her. She began by saying what had
happened, and how these thefts had gone on for some time. She
had said nothing before, hoping that the thief would mend his ways;
but the matter had gone on long enough, and she was going to curse
the thief, as nothing, she felt sure, would make him give up his evil
ways. She called on all the spirits of the waters and the hills and the
air to listen to her words and to aid her. She began quietly, but
became more excited as she went on. She said something of this
kind:
“ ‘If the thief be a man, may he be unfortunate in
Curses on a man all he undertakes! May he suffer from a disease
thief.
that does not kill him, but makes him helpless—
always in pain—and a burden to others. May his wife be unfaithful to
him, and his children become as lazy and dishonest as he is himself.
If he go out on the war-path, may he be killed, and his head smoked
over the enemy’s fire. If he be boating, may his boat be swamped
and may he be drowned. If he be out fishing, may an alligator kill him
suddenly, and may his relatives never find his body. If he be cutting
down a tree in the jungle, may the tree fall on him and crush him to
death. May the gods curse his farm so that he may have no crops,
and have nothing to eat, and when he begs for food, may he be
refused, and die of starvation.
“ ‘If the thief be a woman, may she be childless,
Curses on a woman or if she happen to be with child let her be
thief.
disappointed, and let her child be still-born, or,
better still, let her die in childbirth. May her husband be untrue to her,
and despise her and ill-treat her. May her children all desert her if
she live to grow old. May she suffer from such diseases as are
peculiar to women, and may her eyesight grow dim as the years go
on, and may there be no one to help her or lead her about when she
is blind.’
“I have only given the substance of what she said; but I shall never
forget the silence and the awed faces of those who heard her. I left
the house early next morning, so I do not know what was the result
of her curse—whether the thief confessed or not.”36.1
 The ancient Greeks seem to have made a very
Thieves cursed in liberal use of curses as a cheap and effective
ancient Greece.
mode of protecting property, which dispenses the
injured party from resorting to the tedious, expensive, and too often
fruitless formalities of the law. These curses they inscribed on tablets
of lead and other materials and deposited either in the place which
was to be protected from depredation or in the temple of the god to
whose tender mercies the criminal was committed. For example, in a
sacred precinct dedicated to Demeter, Persephone, Pluto and other
deities of a stern and inflexible temper at Cnidus, a number of leaden
tablets were found inscribed with curses which consigned the
malefactors of various sorts to the vengeance of the two Infernal
Goddesses, Demeter and her daughter. “May he or she never find
Persephone propitious!” is the constantly repeated burden of these
prayers; and in some of them the sinner is not only excommunicated
in this world but condemned to eternal torments in the world
hereafter. Often the persons who launched these curses were ladies.
One irate dame consigns to perdition the thief who had stolen her
bracelet or the defaulter who had failed to send back her
underclothes.36.2 Another curse, engraved on a marble slab found at
Smyrna, purports that if any man should steal one of the sacred
vessels of a certain goddess or injure her sacred fish, he may die a
painful death, devoured by the fishes.36.3 Sometimes, apparently,
these Greek imprecations were as effective in reclaiming sinners as
Dyak curses are to this day. Thus we read of a curious dedication to
a lunar deity of Asia Minor, by name Men Aziottenos, which declares
how one Artemidorus, having been reviled by a couple of rude
fellows, cursed them in a votive tablet, and how one of the culprits,
having been punished by the god, made a propitiatory offering and
mended his wicked ways.37.1 To prevent people
Landmarks
protected by gods
from encroaching on their neighbours’ land by
and curses. removing the boundary stones, the Greeks
committed landmarks to the special protection of
the great god Zeus;37.2 and Plato dwells with unction on the double
punishment, divine and human, to which the sinner exposed himself
who dared to tamper with these sacred stones.37.3 The Romans
went even further, for they created a god for the sole purpose of
looking after landmarks, and he must have had his hands very full if
he executed all the curses which were levelled not only at every man
who shifted his neighbour’s boundary stone, but even at the oxen
which he employed to plough up his neighbour’s land.37.4 The
Hebrew code of Deuteronomy pronounced a solemn curse on such
as removed their neighbour’s landmarks;37.5 and Babylonian kings
exhausted their imagination in pouring out a flood of imprecations
against the abandoned wretch who thus set at naught the rights of
property in land.37.6 King Nebuchadnezzar in particular, before he
was turned out to grass, appears to have distinguished himself by
the richness and variety of his execrations, if we may judge by a
specimen of them which has survived. A brief extract from this
masterpiece may serve to illustrate the king’s style of minatory
eloquence. Referring to the bold bad man, “be it shepherd or
governor, or agent or regent, levy master or magistrate,” whosoever
he might be, who “for all days to come, for the future of human
habitations,” should dare to tamper with the land which his Majesty
had just marked out, “Ninib, lord of boundaries and boundary-stones,
tear out his boundary stone. Gula, great lady, put lingering illness
into his body, that dark and light red blood he may pour out like
water. Ishtar, lady of countries, whose fury is a flood, reveal
difficulties to him, that he escape not from misfortune. Nusku, mighty
lord, powerful burner, the god, my creator, be his evil demon and
may he burn his root. Whoever removes this stone, in the dust hides
it, burns it with fire, casts it into water, shuts it up in an enclosure,
causes a fool, a deaf man, an idiot to take it, places it in an invisible
place, may the great gods, who upon this stone are mentioned by
their names, curse him with an evil curse, tear out his foundation and
destroy his seed.”38.1
In Africa also superstition is a powerful ally of
Superstition as an the rights of private property. Thus the Balonda
ally of the rights of
private property in place beehives on high trees in the forest and
Africa. protect them against thieves by tying a charm or
“piece of medicine” round the tree-trunks. This
proves a sufficient protection. “The natives,” says Livingstone,
“seldom rob each other, for all believe that certain medicines can
inflict disease and death; and though they consider that these are
only known to a few, they act on the principle that it is best to let
them all alone. The gloom of these forests strengthens the
superstitious feelings of the people. In other quarters, where they are
not subjected to this influence, I have heard the chiefs issue
proclamations to the effect, that real witchcraft medicines had been
placed at certain gardens from which produce had been stolen; the
thieves having risked the power of the ordinary charms previously
placed there.”38.2
The Wanika of East Africa “believe in the power
The Wanika of East and efficacy of charms and amulets, and they
Africa.
wear them in great variety; legs, arms, neck, waist,
hair, and every part of the body are laden with them, either for the
cure or prevention of disease; for the expulsion or repulsion of evil
spirits; and to keep at bay snakes, wild animals, and every other evil.
They hang painted calabashes from the baobab at their hut doors to
keep away thieves; shells, dolls, eggs scratched over with Arabic
characters by the Wana Chuoni (sons of the book) of the coast, are
placed about their plantations and in their fruit-trees, and they
believe that death would overtake a thief who should disregard them.
A charm bound to the leg of a fowl is ample protection for the village.
There is no doubt that, superstitious as the people are, they dread
running great risks for the sake of small gains, and so these charms
answer their purpose.”39.1 Among the Boloki of the
The Boloki of the
Congo.
Upper Congo, when a woman finds that the
cassava roots, which she keeps soaking in a
water-hole, are being stolen, she takes a piece of gum copal, and
fixing it in the cleft of a split stick she puts it on the side of the hole,
while at the same time she calls down a curse on the thief. If the thief
is a man, he will henceforth have no luck in fishing; if she is a
woman, she will have no more success in farming.39.2 The Ekoi of
Southern Nigeria protect their farms against thieves by bundles of
palm leaves to which they give the name of okpata. Should any one
steal from a farm thus protected, he will fall sick and will not recover
unless he gives a certain dance, to which the name of okpata is also
applied.39.3
 In the mountains of Marrah, a district of Darfur,
Guardian spirits houses, goods, and cattle are protected against
(damzogs) of
property in Darfur. thieves by certain fierce and dangerous guardian-
spirits called damzogs, which can be bought like
watch dogs. Under the guardianship of such a spiritual protector the
sheep and cows are left free to wander at will; for if any one were
rash enough to attempt to steal or kill one of the beasts, his hand
with the knife in it would remain sticking fast to the animal’s throat till
the owner came and caught the rascal. An Arab merchant, travelling
in Darfur, received from a friend the following account of the way to
procure one of these useful guardians. “At the time when I first
began to trade, my friend, I often heard that damzogs could be
bought and sold, and that to procure one I must apply to the owner
of a damzog, and discuss the price with him. When the bargain is
concluded, it is necessary to give a large gourd of milk to the seller,
who takes it to his house, where are his damzogs. On entering he
salutes them, and goes and hangs up his vase to a hook, saying,
—‘One of my friends—such a one—very rich, is in fear of robbers,
and asks me to supply him with a guardian. Will one of you go and
live in his house? There is plenty of milk there, for it is a house of
blessing, and the proof thereof is, that I bring you this kara of milk.’
The damzogs at first refuse to comply with the invitation. ‘No, no,’
say they, ‘not one of us will go.’ The master of the hut conjures them
to comply with his desires, saying, ‘Oh! let the one that is willing
descend into the kara.’ He then retires a little, and presently one of
the damzogs is heard to flop into the milk, upon which he hastens
and claps upon the vase a cover made of date-leaves. Thus stopped
up he unhooks the kara, and hands it over to the buyer, who takes it
away and hangs it on the wall of his hut, and confides it to the care
of a slave or of a wife, who every morning comes and takes it,
emptying out the milk, washing it and replenishing it, and hanging it
up again. From that time forward the house is safe from theft or
loss.” The merchant’s informant, the Shereef Ahmed Bedawee, had
himself purchased one of these guardian spirits, who proved most
vigilant and efficient in the discharge of his duties; indeed his zeal
was excessive, for he not only killed several slaves who tried to rob
his master, but did summary execution on the Shereef’s own son,
when the undutiful young man essayed to pilfer from his father’s
shop. This was too much for the Shereef; he invited a party of friends
to assist him in expelling the inflexible guardian. They came armed
with guns and a supply of ammunition, and by raking the shop with
repeated volleys of musketry they at last succeeded in putting the
spirit to flight.40.1
Amongst the Nandi of British East Africa nobody
The curses of dares to steal anything from a smith; for if he did,
smiths and potters.
the smith would heat his furnace, and as he blew
the bellows to make the flames roar he would curse the thief so that
he would die. And in like manner among these people, with whom
the potters are women, nobody dares to filch anything from a potter;
for next time she heated her wares the potter would curse him,
saying, “Burst like a pot, and may thy house become red,” and the
thief so cursed would die.41.1 In Loango, when a
Charms to protect
property in West
man is about to absent himself from home for a
Africa. considerable time he protects his hut by placing a
charm or fetish before it, consisting perhaps of a
branch with some bits of broken pots or trash of that sort; and we are
told that even the most determined robber would not dare to cross a
threshold defended by these mysterious signs.41.2 On the coast of
Guinea fetishes are sometimes inaugurated for the purpose of
detecting and punishing certain kinds of theft; and not only the culprit
himself, but any person who knows of his crime and fails to give
information is liable to be punished by the fetish. When such a fetish
is instituted, the whole community is warned of it, so that he who
transgresses thereafter does so at his peril. For example, a fetish
was set up to prevent sheep-stealing and the people received
warning in the usual way. Shortly afterwards a slave, who had not
heard of the law, stole a sheep and offered to divide it with a friend.
The friend had often before shared with him in similar enterprises,
but the fear of the fetish was now too strong for him; he informed on
the thief, who was brought to justice and died soon after of a
lingering and painful disease. Nobody in the country ever doubted
but that the fetish had killed him.41.3 Among the Ewe-speaking tribes
of the Slave Coast in West Africa houses and household property
are guarded by amulets (võ-sesao), which derive their virtue from
being consecrated or belonging to the gods. The crops, also, in
solitary glades of the forest are left under the protection of such
amulets, generally fastened to long sticks in some conspicuous
position; and so guarded they are quite safe from pillage. By the side
of the paths, too, may be seen food and palm-wine lying exposed for
sale with nothing but a charm to protect them; a few cowries placed
on each article indicate its price. Yet no native would dare to take the
food or the wine without depositing its price; for he dreads the
unknown evil which the god who owns the charm would bring upon
him for thieving.42.1 In Sierra Leone charms, called greegrees, are
often placed in plantations to deter people from stealing, and it is
said that “a few old rags placed upon an orange tree will generally,
though not always, secure the fruit as effectually as if guarded by the
dragons of the Hesperides. When any person falls sick, if, at the
distance of several months, he recollects having stolen fruit, etc., or
having taken it softly as they term it, he immediately supposes
wangka has caught him, and to get cured he must go or send to the
person whose property he had taken, and make to him whatever
recompense he demands.”42.2
Superstitions of the same sort have been
Charms to protect transported by the negroes to the West Indies,
property in the West
Indies. where the name for magic is obi and the magician
is called the obeah man. There also, we are told,
the stoutest-hearted negroes “tremble at the very sight of the ragged
bundle, the bottle or the egg-shells, which are stuck in the thatch or
hung over the door of a hut, or upon the branch of a plantain tree, to
deter marauders.… When a negro is robbed of a fowl or a hog, he
applies directly to the Obeah-man or woman; it is then made known
among his fellow blacks, that obi is set for the thief; and as soon as
the latter hears the dreadful news, his terrified imagination begins to
work, no resource is left but in the superior skill of some more
eminent Obeah-man of the neighbourhood, who may counteract the
magical operations of the other; but if no one can be found of higher
rank and ability; or if, after gaining such an ally, he should still fancy
himself affected, he presently falls into a decline, under the incessant
horror of impending calamities. The slightest painful sensation in the
head, the bowels, or any other part, any casual loss or hurt, confirms
his apprehensions, and he believes himself the devoted victim of an
invisible and irresistible agency. Sleep, appetite and cheerfulness
forsake him; his strength decays, his disturbed imagination is
haunted without respite, his features wear the settled gloom of
despondency: dirt, or any other unwholesome substance, becomes
his only food, he contracts a morbid habit of body, and gradually
sinks into the grave.”43.1 Superstition has killed him.
Similar evidence might doubtless be multiplied,
Conclusion. but the foregoing cases suffice to shew that
among many peoples and in many parts of the
world superstitious fear has operated as a powerful motive to deter
men from stealing. If that is so, then my second proposition may be
regarded as proved, namely, that among certain races and at certain
times superstition has strengthened the respect for private property
and has thereby contributed to the security of its enjoyment.
 IV.
MARRIAGE

I pass now to my third proposition, which is, that

Superstition as a among certain races and at certain times
prop of sexual
morality. superstition has strengthened the respect for
marriage, and has thereby contributed to a stricter
observance of the rules of sexual morality both among the married
and the unmarried. That this is true will appear, I think, from the
following instances.
Among the Karens of Burma “adultery, or
Adultery or fornication, is supposed to have a powerful
fornication
supposed by the influence to injure the crops. Hence, if there have
Karens to blight the been bad crops in a village for a year or two, and
crops. the rains fail, the cause is attributed to secret sins
of this character, and they say the God of heaven
and earth is angry with them on this account; and all the villagers
unite in making an offering to appease him.” And
Pig’s blood used to when a case of adultery or fornication has come to
expiate the crime.
light, “the elders decide that the transgressors
must buy a hog, and kill it. Then the woman takes one foot of the
hog, and the man takes another, and they scrape out furrows in the
ground with each foot, which they fill with the blood of the hog. They
next scratch the ground with their hands and pray: ‘God of heaven
and earth, God of the mountains and hills, I have destroyed the
productiveness of the country. Do not be angry with me, do not hate
me; but have mercy on me, and compassionate me. Now I repair the
mountains, now I heal the hills, and the streams and the lands. May
there be no failure of crops, may there be no unsuccessful labours,
or unfortunate efforts in my country. Let them be dissipated to the
foot of the horizon. Make thy paddy fruitful, thy rice abundant. Make
the vegetables to flourish. If we cultivate but little, still grant that we
may obtain a little.’ After each has prayed thus, they return to the
house and say they have repaired the earth.”45.1 Thus, according to
the Karens adultery and fornication are not simply moral offences
which concern no one but the culprits and their families: they
physically affect the course of nature by blighting the earth and
destroying its fertility; hence they are public crimes which threaten
the very existence of the whole community by cutting off its food
supplies at the root. But the physical injury which these offences do
to the soil can be physically repaired by saturating it with pig’s blood.
Some of the tribes of Assam similarly trace a
Disastrous effects connexion between the crops and the behaviour of
ascribed to sexual
crime in Assam, the human sexes; for they believe that so long as
Bengal, and the crops remain ungarnered, the slightest
Annam.
incontinence would ruin all.45.2 Again, the
inhabitants of the hills near Rajamahal in Bengal imagine that
adultery, undetected and unexpiated, causes the inhabitants of the
village to be visited by a plague or destroyed by tigers or other
ravenous beasts. To prevent these evils an adulteress generally
makes a clean breast. Her paramour has then to furnish a hog, and
he and she are sprinkled with its blood, which is supposed to wash
away their sin and avert the divine wrath. When a village suffers from
plague or the ravages of wild beasts, the people religiously believe
that the calamity is a punishment for secret immorality, and they
resort to a curious form of divination to discover the culprits, in order
that the crime may be duly expiated.45.3 The Khasis of Assam are
divided into a number of clans which are exogamous, that is to say,
no man may marry a woman of his own clan. Should a man be found
to cohabit with a woman of his own clan, it is treated as incest and is
believed to cause great disasters; the people will be struck by
lightning or killed by tigers, the women will die in child-bed, and so
forth. The guilty couple are taken by their clansmen to a priest and
obliged to sacrifice a pig and a goat; after that they are made
outcasts, for their offence is inexpiable.46.1 The Orang Glai, a savage
tribe in the mountains of Annam, similarly suppose that illicit love is
punished by tigers, which devour the sinners. If a girl is found with
child, her family offers a feast of pigs, fowls, and wine to appease the
offended spirits.46.2
The Battas of Sumatra in like manner think that if an unmarried
woman is with child, she must be given in marriage at once, even to
 a man of lower rank; for otherwise the people will
Similar views held be infested with tigers, and the crops in the fields
by the Battas of
Sumatra. will not be abundant. They also believe that the
adultery of married women causes a plague of
tigers, crocodiles, or other wild beasts. The crime of incest, in their
opinion, would blast the whole harvest, if the wrong were not
speedily repaired. Epidemics and other calamities that affect the
whole people are almost always traced by them to incest, by which is
to be understood any marriage that conflicts with their customs.46.3
The natives of Nias, an island to the west of Sumatra, imagine that
heavy rains are caused by the tears of a god weeping at the
commission of adultery or fornication. The punishment for these
crimes is death. The two delinquents, man and woman, are buried in
a narrow grave with only their heads projecting above ground; then
their throats are stabbed with a spear or cut with a knife, and the
grave is filled up. Sometimes, it is said, they are buried alive.
However, the judges are not always incorruptible and the injured
family not always inaccessible to the allurement of gain; and
pecuniary compensation is sometimes accepted as a sufficient salve
for wounded honour. But if the wronged man is a chief, the culprits
must surely die. As a consequence, perhaps, of this severity, the
crimes of adultery and fornication are said to be far less frequent in
Nias than in Europe.47.1
Similar views prevail among many tribes in
Similar views Borneo. Thus in regard to the Sea Dyaks we are
among the tribes of
Borneo. told by Archdeacon Perham that “immorality
among the unmarried is supposed to bring a
plague of rain upon the earth, as a punishment inflicted by Petara. It
must be atoned for with sacrifice and fine. In a
Excessive rains function which is sometimes held to procure fine
thought by the
Dyaks to be caused weather, the excessive rain is represented as the
by sexual offences. result of the immorality of two young people.
Petara is invoked, the offenders are banished from
their home, and the bad weather is said to cease. Every district
traversed by an adulterer is believed to be accursed of the gods until
the proper sacrifice has been offered.”47.2 When rain pours down day
after day and the crops are rotting in the fields, these Dyaks come to
the conclusion that some people have been secretly indulging in
lusts of the flesh; so the elders lay their heads together and
adjudicate on all cases of incest and bigamy, and purify the earth
with the blood of pigs, which appears to these
Blood of pigs shed savages, as sheep’s blood appeared to the
to expiate incest
and unchastity. ancient Hebrews, to possess the valuable property
of atoning for moral guilt. Not long ago the
offenders, whose lewdness had thus brought the whole country into
danger, would have been punished with death or at least slavery. A
Dyak may not marry his first cousin unless he first performs a special
ceremony called bergaput to avert evil consequences from the land.
The couple repair to the water-side, fill a small pitcher with their
personal ornaments, and sink it in the river; or instead of a jar they
fling a chopper and a plate into the water. A pig is then sacrificed on
the bank, and its carcase, drained of blood, is thrown in after the jar.
Next the pair are pushed into the water by their friends and ordered
to bathe together. Lastly, a joint of bamboo is filled with pig’s blood,
and the couple perambulate the country and the villages round
about, sprinkling the blood on the ground. After that they are free to
marry. This is done, we are told, for the sake of the whole country, in
order that the rice may not be blasted by the marriage of cousins.48.1
Again, we are informed that the Sibuyaus, a Dyak tribe of Sarawak,
are very careful of the honour of their daughters, because they
imagine that if an unmarried girl is found to be with child it is
offensive to the higher powers, who, instead of always chastising the
culprits, punish the tribe by visiting its members with misfortunes.
Hence when such a crime is detected they fine the lovers and
sacrifice a pig to appease the angry powers and to avert the
sickness or other calamities that might follow. Further, they inflict
fines on the families of the couple for any severe accident or death
by drowning that may have happened at any time within a month
before the religious atonement was made; for they regard the
families of the culprits as responsible for these mishaps. The fines
imposed for serious or fatal accidents are heavy; for simple wounds
they are lighter. With the fear of these fines before their eyes parents
keep a watchful eye on the conduct of their daughters. Among the
Dyaks of the Batang Lupar river the chastity of the unmarried girls is
not so strictly guarded; but in respectable families, when a daughter
proves frail, they sacrifice a pig and sprinkle its blood on the doors to
wash away the sin.48.2 The Hill Dyaks of Borneo abhor incest and do
not allow the marriage even of cousins. In 1846 the Baddat Dyaks
complained to Mr. Hugh Low that one of their chiefs had disturbed
the peace and prosperity of the village by marrying his own
granddaughter. Since that disastrous event, they said, no bright day
had blessed their territory; rain and darkness alone prevailed, and
unless the plague-spot were removed, the tribe would soon be
ruined. The old sinner was degraded from office, but apparently
allowed to retain his wife; and the domestic brawls between this ill-
assorted couple gave much pain to the virtuous villagers.49.1
Among the pagan tribes of Borneo in general,
Incest punished but of Sarawak in particular, “almost all offences
with death by the
pagan tribes of are punished by fines only. Of the few offences
Borneo. which are felt to require a heavier punishment, the
one most seriously regarded is incest. For this
offence, which is held to bring grave peril to the whole house,
especially the danger of starvation through failure of the padi crop,
two punishments have been customary. If the guilt of the culprits is
perfectly clear, they are taken to some open spot on the river-bank at
some distance from the house. There they are thrown together upon
the ground and a sharpened bamboo stake is driven through their
bodies, so that they remain pinned to the earth. The bamboo, taking
root and growing luxuriantly on this spot, remains as a warning to all
who pass by; and, needless to say, the spot is looked on with horror
and shunned by all men. The other method of punishment is to shut
up the offenders in a strong wicker cage and to throw them into the
river. This method is resorted to as a substitute for the former one,
owing to the difficulty of getting any one to play the part of
executioner and to drive in the stake, for this involves the shedding
of the blood of the community. The kind of incest most commonly
committed is the connection of a man with an adopted daughter, and
(possibly on account of this frequency) this is the kind which is most
strongly reprobated.… The punishment of the incestuous couple
does not suffice to ward off the danger brought by them upon the
community. The household must be purified with the blood of pigs
and fowls; the animals used are the property of the offenders or of
their family; and in this way a fine is imposed. When any calamity
threatens or falls upon a house, especially a great rising of the river
which threatens to sweep away the house or the tombs of the
household, the Kayans are led to suspect that incestuous
intercourse in their own or in neighbouring houses has taken place;
and they look round for evidences of it, and sometimes detect a case
which otherwise would have remained hidden. It seems probable
that there is some intimate relation between this belief and the
second of the two modes of punishment described above; but we
have no direct evidence of such connection. All the other peoples
also, except the Punans, punish incest with death. Among the Sea
Dyaks the most common form of incest is that between a youth and
his aunt, and this is regarded at least as seriously as any other
form.”50.1
Nor is it the heinous crime of incest alone which
Evil and confusion in the opinion of the Sea Dyaks endangers the
supposed by the
Dyaks to be whole community. The same effect is supposed to
wrought by follow whenever an unmarried woman is found
fornication. with child and cannot or will not name her seducer.
“The greatest disgrace,” we are told, “is attached
to a woman found in a state of pregnancy, without being able to
name her husband; and cases of self-poisoning, to avoid the shame,
are not of unusual occurrence. If one be found in this state, a fine
must be paid of pigs and other things. Few even of the chiefs will
come forward without incurring considerable responsibility. A pig is
killed, which nominally becomes the father, for want, it is supposed,
of another and better one. Then the surrounding neighbours have to
be furnished with a share of the fine to banish the Jabu, which exists
after such an event. If the fine be not forthcoming, the woman dare
not move out of her room, for fear of being molested, as she is
supposed to have brought evil (kudi) and confusion upon the
inhabitants and their belongings.”50.2
The foregoing accounts refer especially to the
Similar beliefs and tribes of Borneo under British rule; but similar
customs among the
tribes of Dutch ideas and customs prevail among the kindred
Borneo. tribes of Dutch Borneo. Thus the Kayans or
Bahaus in the interior of the island believe that adultery is punished
by the spirits, who visit the whole tribe with failure of the crops and
other misfortunes. Hence in order to avert these evil consequences
from the innocent members of the tribe, the two culprits, with all their
possessions, are first placed on a gravel bank in the middle of the
river, in order to isolate or, in electrical language, to insulate them
and so prevent the moral or rather physical infection from spreading.
Then pigs and fowls are killed, and with the blood priestesses smear
the property of the guilty pair in order to disinfect it. Finally, the two
are placed on a raft, with sixteen eggs, and allowed to drift down
stream. They may save themselves by plunging into the water and
swimming ashore; but this is perhaps a mitigation of an older
sentence of death by drowning, for young people still shower long
grass stalks, representing spears, at the shamefaced and dripping
couple.51.1 Certain it is, that some Dyak tribes used to punish incest
by fastening the man and woman in separate baskets laden with
stones and drowning them in the river. By incest they understood the
cohabitation of parents with children, of brothers with sisters, and of
uncles and aunts with nieces and nephews. A Dutch resident had
much difficulty in saving the life of an uncle and niece who had
married each other; finally he procured their banishment to a distant
part of Borneo.51.2 The Blu-u Kayans, another tribe in the interior of
Borneo, believe that an intrigue between an unmarried pair is
punished by the spirits with failure of the harvest, of the fishing, and
of the hunt. Hence the delinquents have to appease the wrath of the
spirits by sacrificing a pig and a certain quantity of rice.51.3 In Pasir, a
district of Eastern Borneo, incest is thought to bring dearth,
epidemics, and all sorts of evils on the land.51.4 In the island of
Ceram a man convicted of unchastity has to smear every house in
the village with the blood of a pig and a fowl: this is supposed to wipe
out his guilt and ward off misfortunes from the village.51.5
When the harvest fails in Southern Celebes, the
Failure of the crops Macassars and Bugineese regard it as a sure sign
and other disasters
thought to be that incest has been committed and that the spirits
caused by incest in are angry. In the years 1877 and 1878 it happened
Celebes. that the west monsoon did not blow and that the
rice crop in consequence came to nothing; moreover many buffaloes
died of a murrain. At the same time there was in the gaol at Takalar a
prisoner, who had been formerly accused of incest. Some of the
people of his district begged the Dutch governor to give the criminal
up to them, for according to the general opinion the plagues would
never cease till the guilty man had received the punishment he
deserved. All the governor’s powers of persuasion were needed to
induce the petitioners to return quietly to their villages; and when the
prisoner, having served his time, was released shortly afterwards, he
was, at his own request, given an opportunity of sailing away to
another land, as he no longer felt safe in his own country.52.1 Even
when the incestuous couple has been brought to
Disastrous effects justice, their blood may not be shed; for the people
supposed to follow
from shedding the think that, were the ground to be polluted by the
blood of incestuous blood of such criminals, the rivers would dry up
couples on the and the supply of fish would run short, the harvest
ground.
and the produce of the gardens would miscarry,
edible fruits would fail, sickness would be rife among cattle and
horses, civil strife would break out, and the country would suffer from
other widespread calamities. Hence the punishment of the guilty is
such as to avoid the spilling of their blood: usually they are tied up in
a sack and thrown into the sea to drown. Yet they get on their
journey to eternity the necessary provisions, consisting of a bag of
rice, salt, dried fish, coco-nuts, and other things, among which three
quids of betel are not forgotten.52.2 We can now perhaps understand
why the Romans used to sew up a parricide in a sack with a dog, a
cock, a viper, and an ape for company, and fling him into the sea.
They probably feared to defile the soil of Italy by spilling upon it the
blood of such a miscreant.52.3 Amongst the Tomori of Central
Celebes a person guilty of incest is throttled; no drop of his blood
may fall on the ground, for if it did, the rice would never grow again.
The union of uncle with niece is regarded by these people as incest,
but it can be expiated by an offering. A garment of the man and one
of the woman are laid on a copper vessel; the blood of a sacrificed
animal, either a goat or a fowl, is allowed to drip on the garments,
and then the vessel with its contents is set floating down the river.53.1
Among the Tololaki, another tribe of Central Celebes, persons who
have defiled themselves with incest are shut up in a basket and
drowned. No drop of their blood may be spilt on the ground, for that
would hinder the earth from ever bearing fruit again.53.2 Among the
Bare’e-speaking Toradjas of Central Celebes in general the penalty
for incest, that is for the sexual intercourse of parents with children or
of brothers with sisters, is death. But whereas the death-sentence for
adultery is executed with a spear or a sword, the death-sentence for
incest is usually executed among the inland tribes by clubbing or
throttling; for were the blood of the culprits to drip on the ground, the
earth would be rendered barren. The people on the coast put the
guilty pair in a basket, weight it with stones, and fling it into the sea.
This prescribed manner of putting the incestuous to death, we are
informed, makes the execution very grievous. However, the writers
who furnish us with these particulars and who have lived among the
people on terms of intimacy for many years, add that “incest seldom
occurs, or rather the cases that come to light are very few.”53.3 In
some districts of Central Celebes, the marriage of cousins, provided
they are children of two sisters, is forbidden under pain of death; the
people think that such an alliance would anger the spirits, and that
the rice and maize harvests would fail. Strictly speaking, two such
cousins who have committed the offence should be tied together,
weighted with stones, and thrown into water to drown. In practice,
however, the culprits are spared and their sin expiated by shedding
the blood of a buffalo or a goat. The blood is mixed with water and
sprinkled on the rice-fields or poured on the maize-fields, no doubt in
order to appease the angry spirits and restore its fertility to the tilled
land. The natives of these districts believe that were a brother and
sister to commit incest, the ground on which the tribe dwells would
be swallowed up. If such a crime takes place, the guilty pair are tied
together, their feet weighted with stones, and thrown into the sea.54.1
When it rains in torrents, the Galelareese of
Excessive rains, Halmahera, another large East Indian island, say
earthquakes, and
volcanic eruptions that brother and sister, or father and daughter, or
supposed to be in short some near kinsfolk are having illicit
produced by incest relations with each other, and that every human
in Halmahera.
being must be informed of it, for then only will the
rain cease to descend. The superstition has repeatedly caused blood
relations to be accused, rightly or wrongly, of incest. Further, the
people think that alarming natural phenomena, such as a violent
earthquake or the eruption of a volcano, are caused by crimes of the
same sort. Persons charged with such offences are brought to
Ternate; it is said that formerly they were often drowned on the way
or, on being haled thither, were condemned to be thrown into the
volcano.54.2 In the Banggai Archipelago, to the east of Celebes,
earthquakes are explained as punishments inflicted by evil spirits for
indulgence in illicit love.54.3
In some parts of Africa, also, it is believed that
Breaches of sexual breaches of sexual morality disturb the course of
morality thought to
blight the fruits of nature, particularly by blighting the fruits of the
the earth and earth; and probably such views are much more
otherwise disturb widely diffused in that continent than the scanty
the course of nature
in Africa. and fragmentary evidence at our disposal might
lead us to suppose. Thus, the negroes of Loango,
in West Africa, imagine that the commerce of a man with an
immature girl is punished by God with drought and consequent
famine until the transgressors expiate their transgression by dancing
naked before the king and an assembly of the people, who throw hot
gravel and bits of glass at the pair as they run the gauntlet. The rains
in that country should fall in September, but in 1898 there was a long
drought, and when the month of December had nearly passed, the
sun-scorched stocks of the fruitless Indian corn shook their rustling
leaves in the wind, the beans lay shrivelled and black on the ruddy
soil, and the shoots of the sweet potato had flowered and withered
long ago. The people cried out against their rulers for neglecting their
duty to the primeval powers of the earth; the priests of the sacred
groves had recourse to divination and discovered that God was
angry with the land on account of the immorality of certain persons
unknown, who were not observing the traditions and laws of their
God and country. The feeble old king had fled, but the slave who
acted as regent in his room sent word to the chiefs that there were
people in their towns who were the cause of God’s wrath. So every
chief called his subjects together and caused enquiries to be made,
and then it was discovered that three girls had broken the customs of
their country; for they were with child before they had passed
through what is called the paint-house, that is, before they had been
painted red and secluded for a season in token that they had
attained to the age of puberty. The people were incensed and
endeavoured to punish or even kill the three girls; and the English
writer who has recorded the case has thought it worth while to add
that on the very morning when the culprits were brought before the
magistrate rain fell.55.1 Amongst the Bavili of Loango, who are
divided into totemic clans, no man is allowed to marry a woman of
his mother’s clan; and God is believed to punish a breach of this
marriage law by withholding the rains in their due season.56.1 Similar
notions of the blighting influence of sexual crime appear to be
entertained by the Nandi of British East Africa; for we are told that
when a warrior has got a girl with child, she “is punished by being put
in Coventry, none of her girl friends being allowed to speak to or look
at her until after the child is born and buried. She
Sexual purity is also regarded with contempt for the rest of her
required of those
who handle corn or life and may never look inside a granary for fear of
enter a granary. spoiling the corn.”56.2 Among the Basutos in like
manner “while the corn is exposed to view, all
defiled persons are carefully kept from it. If the aid of a man in this
state is necessary for carrying home the harvest, he remains at
some distance while the sacks are filled, and only approaches to
place them upon the draught oxen. He withdraws as soon as the
load is deposited at the dwelling, and under no pretext can he assist
in pouring the corn into the basket in which it is preserved.”56.3 The
nature of the defilement which thus disqualifies a man from handling
the corn is not mentioned, but we may conjecture that unchastity
would fall under this general head. For amongst the Basutos after a
child is born a fresh fire has to be kindled in the dwelling by the
friction of wood, and this must be done by a young man of chaste
habits; it is believed that an untimely death awaits him who should
dare to discharge this holy office after having lost his innocence.56.4
In Morocco whoever enters a granary must first remove his slippers
and must be sexually clean. Were an unclean person to enter, the
people believe not only that the grain would lose its blessed
influence (baraka), but that he himself would fall ill. A Berber told Dr.