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IMMUNOLOGY
ABOUT THE AUTHOR
Dr S R Ramesh is currently serving as Professor in University of

Mysore, Mysuru, Karnataka. After obtaining PhD degree from
University of Mysore in 1980, he briefly served as Research
Officer at the ICMR institution Vector Control Research Centre,
Puducherry. His interest and passion for teaching prompted
him to come back to the Department of Studies in Zoology
at Manasagangotri, University of Mysore, Mysuru, as a Lecturer
in 1981.
Dr Ramesh has also worked as post-doctoral fellow at Institut
für Genetik, Ruhr Universität Bochum, Bochum, Germany
with fellowship from Deutscher Akademischer Austauschdienst
(DAAD), Germany. Later, he worked as visiting fellow at Institut
für Genetik, Ruhr Universität, Bochum and at Institut für Genetik,
Heinrich-Heine Universität, Dusseldorf, Germany. In recognition of
his post-doctoral work, the Deutsche Gesellschaft für Technische Zusammenarbeit (GTZ), Germany
supported him to continue his research work that was initiated in Germany by providing laboratory
equipment when he came back to India.
With research grants from University Grants Commission, Department of Science & Technology
and Department of Atomic Energy, he chose to work on Drosophila as a model organism to study
biochemical genetics of larval and pupal salivary gland proteins, adult male accessory gland secretory
proteins, mutations and behavioral differentiation. Five years ago, he initiated work related to learning
and memory in Drosophila and also on screening and understanding the influence of phytochemicals
on biochemical and genetic system of normal, transgenic Alzheimer and Parkinson Drosophila models.
He has authored 85 publications including research papers and research reports in reputed national and
international journals, in addition to many popular science articles in Kannada.
He has served as a chairman/member of many committees of the University Grants Commission
(UGC), New Delhi. He has also served as a member of Academic Council, Faculty of Science &
Technology, Institutional Human Ethics committee, various committees of University of Mysore and
as a member of Institutional Bio-safety Committee of CFTRI, Mysuru.
Dr Ramesh holds vast postgraduate teaching experience of over 34 years and has offered courses
in Immunology, Cell Biology, Cytogenetics, Genetics, Molecular Biology, Animal Physiology,
Environmental Biology and Animal Behavior. He has delivered many special lectures in different fields
of modern biology at different universities and teacher training programs in various institutions.
IMMUNOLOGY
S R Ramesh
Former Professor
Department of Studies in Zoology
University of Mysore, Mysuru, Karnataka
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Immunology
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Dedicated to
My Alma Mater
University of Mysore
on the occasion of its Centenary Year
&
My Family
for their support and encouragement
&
Faculty and Young Students
who wish to become familiar with immunology
CONTENTS
About the Author ii

Foreword xiii
Preface xv
Prologue… 1
1.1 Introduction 9
1.2 Types of Immunity 10
1.3 Innate Immunity 11
1.4 Specific Acquired Immunity (Adaptive Immunity) 21
1.5 Interaction Between Innate and Adaptive Immunity 25
Summary 27
Short Answer Questions 28
Essay Type Questions 29
2.1 Introduction 30
2.2 Lymphatic System 30
2.3 Primary Lymphoid Organs 32
2.4 Secondary Lymphoid Organs 34
2.5 Germinal Centres 38
2.6 Tertiary Lymphoid Organs 39
Summary 40
3.1 Introduction 42
3.2 Hematopoiesis 43
3.3 Phagocytes 45
3.4 Life History of Macrophages 46
3.5 Functions of Monocytes and Macrophages 47
3.6 Lymphocytes 49
viii Contents
3.7 Dendritic Cells 55

3.8 Basophils 58
3.9 Eosinophils 59
3.10 Study of Human Leukocytes 60
Summary 61
4.1 Introduction 63
4.2 Classification of Antigens 68
4.3 Haptens 68
4.4 Superantigens 69
Summary 70
5.1 Introduction 72
5.2 Structure of Immunoglobulins 73
5.3 Antigen-Antibody Interactions 81
5.4 Antibody Dependent Cell Mediated Cytotoxicity 82
Summary 84
6.1 Introduction 86
6.2 Development of B Cells 89
6.3 Genetic Basis of Immunoglobulin Diversity 93
6.4 Clonal Selection and Cellular Production of Antibodies 105
Summary 108
7.1 Introduction 110

7.2 T Cell Development and Maturation 111
7.3 Structure of TCR 114
7.4 Organization of TCR Genes and Their Rearrangement 115
7.5 T Cell Selection 119
7.6 Effector T cells 121
7.7 Other T Cell Types 127
7.8 TCR and MHC Restriction 129
Summary 131
Essay type questions 132
Contents ix

8.2 MHC Molecules 133
8.3 MHC Polymorphism 140
8.4 Antigen Recognition 140
8.5 Antigen Processing and Presentation 146
8.5 Cross-presentation of Exogenous Antigen 153
8.6 Immunological Synapse 153
8.7 Recognition of Endogenous and Exogenous Antigens 154
8.8 Lipid Antigens 155
Summary 156

9.2 Functions of Complement System 166
9.3 Disorders of Complement System 167
9.4 Classical Pathway Deficiencies 168
9.5 Deficiency of Control Proteins 169
9.6 Complement Receptors 172
9.7 Anaphylotoxin Receptors 172
9.8 Receptors of C3b and its Derivatives 174
Summary 176

10.2 Properties 178
10.3 Types of Cytokines 184
10.4 Cytokine Receptors 189
10.5 Cytokines and Inflammation 192
10.6 Cytokine Therapy 195
Summary 196

11.2 Immunological Tolerance 199
11.3 Autoimmunity 202
11.4 Classification of Autoimmune Diseases 204
11.5 Infectious Agents v/s Autoimmunity 214
x Contents
Summary 216

12.2 Primary Immunodeficiencies 218
12.3 Secondary Immunodeficiencies 231
12.4 Acquired Immunodeficiency Syndrome (AIDS) 232
Summary 242

13.2 Type I Hypersensitivity 246
13.3 Type II Hypersensitivity 257
13.4 Type III Hypersensitivity 261
13.5 Type IV Hypersensitivity 263
Summary 267

14.2 Vaccination 271
14.3 Types of Vaccines 274
14.4 How Do We Get Immunized After Vaccination? 290
Summary 292

15.2 Polyclonal v/s Monoclonal Antibodies 294
15.3 Hybridoma 296
15.4 Applications of Monoclonal Antibodies 300
15.6 Advantages and Disadvantages of Monoclonal Antibodies 307
Summary 308

16.2 Occurrence of Cancer 310
16.3 Tumor Antigens 315
16.4 Antitumor Immune Response 318
Contents xi
16.5 The Paradox: Tumors Elude the Immune System 318

16.6 Cancer Immunotherapy 319
Summary 322
Types of Grafts 325
Radioimmunoassay (RIA) 330

Enzyme Linked Immunosorbent Assay (ELISA) 330
Immunoblotting 333
FOREWORD
I was delighted when Dr Ramesh asked me to write the foreword to his book. Dr Ramesh and I were
postgraduate students in the late 70s in Manasagangotri Campus, University of Mysore, Mysuru, Karnataka
which is a wonderful setting for higher learning. Although we came from different disciplines and
backgrounds we always had interesting, intellectual interactions and that continue now also.
Immunity is the cornerstone of existence of all organisms including humans. In nature, every individual
organism or their community is surrounded by pathogenic and non-pathogenic organisms. We all interact,
defend and/or collaborate with a plethora of micro- or macro-organisms in our environment. It may be
alarming to note that despite our obsession to cleanliness and personal hygiene, every human individual
has more non-human DNA/cells than human DNA/cells. Thus, we are constantly exposed to non-self
environment; our health and disease conditions are dependent on continuing ‘conversations’, ranging from
simple interaction to active war. To participate in these ‘conversations’ all higher organisms including
humans have evolved various strategies of innate and adaptive immunities. The science of understanding
these crucial armaments and strategies is called ‘Immunology’.
Dr Ramesh has been teaching immunology to postgraduate students at the University of Mysore, for
more than two decades. His teachings always made significant impact on young minds, particularly in
this extremely interesting system of complex cellular and molecular network as well as protein-protein
interactions involved in molecular recognition discriminating self from non-self. He has put in lot of efforts
in simplifying and explaining various concepts, phenomena and strategies for easier comprehension. This
book showcases his teaching talent and highlights his passion to train the next generation and get them well-
educated in this interdisciplinary field.
The book covers (a) both fundamental and cutting-edge information in innate and adaptive immunity;
(b) all cellular and protein components and their complementary and collaborative interactions;
(c) their role and implications in autoimmunity, immunodeficiencies and hypersensitivity; and (d) their
applications as in monoclonal antibodies and tumor biology. The key features of the book include Learning
Objectives at the beginning of each chapter, ample illustrations for easy comprehension of the concepts and
mechanisms, boxes highlighting key facts and details, summary and, my favourite, several short answer
questions and essay type questions for students that cover various aspects described in the chapter. The
multiple choice questions at the end of the book, as the icing on the cake, will enhance and test their
understanding. Finally, there are two important appendices; one on transplantation and immune suppression,
and the other on immunoassays.
Overall, I believe this will be an excellent text book for undergraduate and postgraduate students and also
act as a reference book for students of medical and paramedical courses as well as for scientists entering the
field of immunology.
DR R MANJUNATHA KINI
Professor
Department of Biological Sciences
National University of Singapore
PREFACE
Immunology, the study of immune systems, originated when Edward Jenner demonstrated that the
incidence of smallpox can be prevented by introducing a small dose of fluid from cowpox pustule
into people. A greater push for immunology to develop into a distinct branch of biology came from
the work of Louis Pasteur who showed that not only smallpox, but also the incidence of variety of
diseases both in animals and humans can be prevented by immunization with vaccines. Since then,
immunization has saved mankind from sufferings and death emanating from epidemic and debilitating
diseases. Immunology is a field of biology and knowledge of this branch of study has grown leaps and
bounds due to development and advances in biochemical and molecular techniques. Incredible insights
into the nature and molecular mechanisms of interactions that occur between tissues and cells, within
the cells as well as between the cells and, molecules of the immune system have been the basis for rapid
advances of not only immunology but also medicine and pharmacology.
In the beginning of an immunology course, my students often used to express that immunology is
tough and complicated but as they become familiar with a reasonably good comprehension of the basic
concepts, they have always found that “Immunology is Amazing”. These interactions prompted me to
transform my lectures into a book. The content and language in this book has been kept simple for easy
comprehension of concepts, processes, mechanisms and applications that beginners always need. This
book will also be helpful for teachers who wish to become familiar with immunology for graduate or
post-graduate classes and also for venturing into higher levels of learning in immunology.
This book has been organized into two parts. The first part “Immunobiology” comprises 10 chapters
focusing on different components of the immune system. A clear comprehension of the content in
this part will create a mindset to understand and think further about the contents of second part,
“Immunology and Human Health”. The second part comprises 6 chapters that deal with importance
and relevance of the immune system in human health. The last chapter of second part is an overview
on immune system and cancer.
Every chapter begins with an introductory paragraph. Subsequently in addition to basic information,
advanced information distilled from recent review articles has been included with an intention to trigger
thinking in the young minds and to enable them to realize its research and application potential. There
are 78 box items altogether. In every chapter the box items provide clarity of a concept or additional
information in the same field or related field depending on the context. The content in this book has
been further supplemented with tables and figures for providing clarity. Additionally, two appendix
items are included to make the book more comprehensive.
The important pedagogical features are as follows:
● Case studies given in boxed items
● Important terminologies highlighted
● Illustrations: 240
xvi Preface
●Chapter end questions: 326

●Objective type questions: 160
My sincere thanks are due to all the scientists and organizations who have given permission for using
their original figures, which have enhanced the scientific content in this book. I am greatly indebted to
my family members who always were the source of my inspiration. I am thankful to my colleagues,
well wishers and friends, in particular Dr M S Basavaraj, Chief Medical Officer, University Health
Centre and Dr T Shivanandappa, CSIR Emeritus Scientist who always encouraged me by discussions
over the issues related to health and contemporary biology. I acknowledge the assistance of Dr M K
Ramakrishna and Ms Sadhana Mutalik during proof reading of the manuscript.
The support of University of Mysore in my academic endeavors is sincerely acknowledged.
I am extremely happy to contribute this book to the academia at a time when the University of
Mysore is celebrating its centenary year.
Special thanks to the reviewers mentioned here for their valuable feedback and suggestions.
J Kamaleswari
Pacchyappa’s college, Chennai, Tamil Nadu
RC Rajkhowa
Cotton College State University, Guwahati, Assam
NK Ganguly
National Institute of Immunology, New Delhi
RP Singh
Indian Institute of Technology, Roorkee, Uttarakhand
It is my pleasure to work with the McGraw Hill Education team headed by Ms Vibha Mahajan and team
members–Vaishali Thapliyal, Suhaib Ali and Kritika Lakhera, who readily responded to all my queries
that enabled me to finalize this book.
S R RAMESH
Publisher’s Note
McGraw Hill Education (India) invites suggestions and comments from you, all of which can be
sent to info.india@mheducation.com (kindly mention the title and author name in the subject line).
Piracy-related issues may also be reported.
PROLOGUE…
Edward Jenner’s pioneering contributions enabled the eradication

of smallpox from this earth. It is regarded that Jenner’s work laid the
foundation for the establishment of Immunology, its subsequent
development, and progress. Hence, Jenner is also regarded as the
father of Immunology. Smallpox over many centuries devastated
mankind. In the 18th century in Europe, around 4,00,000 people
died of smallpox annually. Those who could recover and survive
were badly disfigured, which was much more frustrating and
agonizing throughout their life. Further, one-third of the survived
lost their vision. Hence, smallpox was otherwise also called
“speckled monster” in 18th century England.
Edward Jenner, a doctor by profession in a county namely
Gloucertershire, in England was also interested in varied branches
of science. He studied geology, conducted investigations on
behaviour of cuckoo, and also carried out experiments on human Edward Jenner (1749-1823)
blood. When he was 13 years old, he was apprenticed to a surgeon (foundersofscience.net)
and apothecary in a place near Bristol. He was fascinated by the
belief that milkmaids in some way remained protected from dreadful smallpox. A remark that he
overheard a milkmaid saying, “I shall never have smallpox for I have had cowpox. I shall never have an
ugly pockmarked face” made him to think loudly and believe that there was some connection between
the milkmaids getting the mild cowpox infection and their resistance to life threatening smallpox.
What is cowpox?
Cowpox is a viral skin disease in cows caused by cowpox virus. The affected cows develop blisters
on udders. The virus is transmitted from cows to humans when the udders are touched while milking
the cow. The symptoms of cowpox infection include appearance of red blisters on the hands of
infected person.
Jenner developed a theory that cowpox not only protected the people against smallpox but also could
be transmitted from one to another as a deliberate mechanism for protecting an individual from smallpox.
Jenner decided to try out the theory he had developed. Jenner met a young milkmaid Sarah Nelms, who
had fresh cowpox lesions on her hands and arms. He persuaded her and collected matter from cowpox
blisters and inoculated it into a young boy James Phipps on 14 May 1796; who subsequently developed
2 Immunology
Victims of smallpox: Left: Extent of suffering during the disease (Content provider: Centers for
Disease Control and Prevention), Right: disfigurement after recovery (Content provider: Centers for
Disease Control and Prevention/Dr. Robinson).
mild fever and discomfort in the axillae. Jenner repeated this process a number of days with a gradual
increase in the amount of matter he introduced into the boy. On 1 July 1796 Jenner inoculated the boy
again the matter and this time not with the matter from cowpox lesion but with the matter from a fresh
smallpox lesion. Phipps never caught smallpox and
Jenner concluded that protection was complete. Thus,
Jenner established a method to prevent the incidence
of disfiguring and often fatal disease smallpox and it
took him twenty years of observation, analysis, and
experimentation by the virtue of which, the current
practice of vaccination took its origin. Jenner decided
to call this new procedure as vaccination (Latin: vacca
= cow) in honour of the part played by Sarah and her
cow ‘Blossom’ in his research. In 1798, after adding
few more cases to his initial experiment, Jenner
published his work as a small booklet titled “An Inquiry
into the Causes and Effects of the Variolae Vaccinae,
a disease discovered in some of the western counties
of England, particularly Gloucestershire and Known Edward Jenner introducing fluid from a
by the Name of Cow Pox”. Jenner’s discovery was cowpox blister into the arm of James Phipps
so successful, that in 1840 the government that was (sblazak.wordpress.com)
Prologue… 3
ruling at that time banned any other treatment for smallpox other than the one described and established
by Jenner. Jenner’s method of preventing the incidence of smallpox spread quickly throughout Europe.
It was nearly 100 years, before the procedure of
vaccination was applied to other diseases also. The French
scientist Louis Pasteur was responsible for initiating such a
work by taking the lead from Edward Jenner. Louis Pasteur
was born in Dôle, France. At the age of 20, he received his
bachelor’s degree in science. At Écôle Normale, Paris he
worked on crystallography for his doctoral degree. When he
was 29 years old, he became the chairman of the department
of chemistry at the University of Strasbourg, Strasbourg,
France where he began studying fermentation. At the age
of 32, Pasteur became professor of chemistry and dean of
sciences at the new University of Lille. At this time, Lille
was the centre of alcohol manufacture in France. Soon after
his arrival at Lille, a producer of vinegar requested Pasteur
for help. The vinegar producer could not understand why his
vinegar made from beet juice sometimes spoiled and wanted
to know how to overcome this problem. Pasteur conducted
a microscopic examination of the beet juice and found that Louis Pasteur (1822–1895)
it contained alcohol and yeast. He suggested that the yeast (www.gardenofpraise.com)
was causing the beet juice to ferment. He also demonstrated
that killing of the yeast without spoiling the product is possible by controlled heating of the beet juice.
This process, called “pasteurization,” was widely employed to preserve a number of foods such as
cheese and milk. Pasteur’s discovery brought tremendous improvements in fermentation and heralded
a new era in the brewing and wine industries. Pasteur was an accomplished scientist. In 1857, he was
appointed Director of Scientific Studies at the Ecôle Normale in Paris.
The extraordinary contributions of Louis Pasteur were development of the germ theory of disease
and the use of vaccines to prevent the diseases. Experiments in his lab on vaccination as a deliberate
attempt to prevent the incidence of a disease began in 1881. At that time, chicken cholera (caused by
what we call today Pasteurella multocida) was a serious problem for farmers. The rapid spread of this
disease would have wiped out the entire flock in just three days. Pasteur had identified the cholera
bacillus and was growing it in pure culture. When injected with the culture, the chicken invariably died
in 48 hours. Unexpected discoveries by accident are not new to science. An incident that occurred in the
laboratory of Louis Pasteur led to the discovery of a vaccine for chicken cholera. Charles Chamberland,
who was working with Pasteur, forgot to inject the ‘disease’ into some chickens and went away on
holiday. When he came back, he saw the jar of bacteria placed on a side in the lab and realized that
he did not do the job that was told. He thought he would inject it into the chickens anyway and made
injections. He was amazed to observe that none of those chickens died; which usually would have
died in 48 hours. He reported his observations to Pasteur. Chamberland was asked to repeat what he
had done but with a fresh culture of chicken cholera germs. In the next set of experiments, they had
two groups; the first group consisted of the chickens that were already injected with old culture and
another group that were not (new batch of chickens). Chamberland injected fresh cultures into these
two groups of chickens. The result was again amazing; the chickens that were previously injected with
the old culture survived; while the other group of chickens that were previously never injected with old
cultures died. So to say, the chickens that were inoculated with the old culture had become resistant
4 Immunology
(immune) to chicken cholera. Pasteur was of the opinion that their bodies had used the weaker strain
of germ to form a defence against the more powerful germs in the fresher culture. When Pasteur saw
these results he realized that he was repeating the work of Jenner that was done 85 years earlier; which
had enabled Jenner to confer immunity to smallpox in humans by vaccinating individuals with a mild
form of cowpox. Pasteur then prepared nonvirulent (attenuated) cultures of chicken cholera vaccines by
growing the cholera bacillus at 42°– 43°C; at which temperature the bacillus is rendered non-infectious.
With this, they had also discovered that a weakened form of a disease can act as a vaccine.
Pasteur further thought, if attenuated cholera bacillus could render chickens resistant to the disease,
injection of an attenuated anthrax bacillus must render the sheep immune to anthrax. By various
techniques involving oxidation and aging, Pasteur found that anthrax vaccines indeed prevented anthrax
in laboratory trials. In April 1881, Pasteur announced that his team was successful in founding a way to
weaken anthrax germs and so could produce a vaccine against anthrax. Overwhelmed by the successes
with anthrax and fowl cholera diseases, Pasteur over the next 2–3 years got involved in identification
and isolation of microbes for many other diseases; including swine erysipelas, childbirth fever, and
pneumonia. The most famous success of Pasteur’s research was the development of a vaccine against
rabies. From the experimental observations, Pasteur conceived the idea and provided evidence that
pathogens could be attenuated or weakened or disabled from causing the disease by exposing them to
environmental insults such as high temperature, oxygen, and chemicals. Though Pasteur proved that
vaccination provided immunity, he did not explain how it worked; may be Pasteur’s priority was to
develop vaccines for a variety of diseases, not to look into the mechanisms of how it worked. At the
age of 46, Pasteur suffered a serious paralytic stroke. He died in 1895 after suffering additional strokes.
He was buried, a national hero, by the French Government. Thus, Edward Jenner laid the foundation
for immunology and Louis Pasteur was the first to initiate the development of the field of immunology,
which now has grown boundless to encompass a variety of disciplines that are related to human health
and welfare.
A group of scientists including Paul Ehrlich, Elie Metchnikoff, Jules Bordet, Emil von Behring led
by Louis Pasteur were responsible to presume the presence of a system in the body which was believed
to defend or protect the body from the invasion and attack of pathogens. They called it as immune
system; which literally means the system that exempts i.e. the system that exempts the body from
the disease. In other words, the immune system was thought to be responsible for providing absolute
protection against an injurious or a disease causing agent.
The immune system is usually compared to a fort and its various cells to soldiers. Now, we know
that it is a remarkable defense system that has evolved in vertebrates to protect them from invading
pathogenic microorganisms. The system is scattered all over the body from top to toe comprising
various organs, tissues, cells, and molecules. The system is capable of recognizing limitless variety of
foreign invaders and has evolved mechanisms to get rid of them. The efficiency of an immune system
lies in its ability to distinguish the “self” and “nonself” molecules. A variety of cells and molecules
precisely orchestrate the complex events that are associated with identification, neutralization and/or
destruction of the invader.
Immunity is the state of protection from infectious disease. It has both innate and adaptive
components. The innate immunity refers to the inherent potential of the system to impart resistance to
pathogens that invade an individual. This type of immunity is accomplished by anatomic, physiologic,
endocytic and phagocytic as well as inflammatory barriers to name a few. The adaptive immunity is an
acquired immunity. It is specific and reflects the presence of a functional immune system, capable of
specifically recognizing and selectively eliminating foreign bodies including microbes. Unlike innate
immunity, acquired immunity is characterized by specificity, diversity, self/nonself recognition, and
memory.
Prologue… 5
To accomplish the defensive tasks, the human blood contains a remarkable variety of cells each one
of them specialized to perform one or more functions during an immune response. They are dendritic
cells, monocytes, neutrophils, eosinophils, basophils, platelets, T cells (T-Lymphocytes), and B cells
(B-Lymphocytes). To enable their aggregation and orchestration of responses to a greater extent, a
number of organs and tissues are roped in by the evolutionary process. They include primary lymphoid
organs (bone marrow and thymus) and secondary lymphoid organs/tissues (adenoids, tonsils, spleen,
lymph nodes, Peyer’s patches, mucosal associated lymphoid tissue, and gut associated lymphoid tissue).
The blood vascular system and lymphatic system serve the function of transport of immunocompetent
cells from one organ to the other and to reinforce the dead cells from the regions where the new ones
are produced and matured. The amazing reality is that, all the immune cells including the red blood
corpuscles originate from a master cell, the blood forming (Hematopoetic) stem cell, residing in the
bone marrow.
The immune responses, whose ultimate outcome is to catch and dispose the unwanted microbe or
molecule, include the following:
(i) Innate immune responses that provide first line of defence. A variety of tissues, cells, and
molecules are involved in this response.
(ii) Cell mediated immune response which includes physical involvement of the cells (Phagocytosis
by Macrophages and Microphages, target cell killing by cytotoxic T cells, NK cells, and NKT
cells) that results in the removal of pathogens and antigens.
(iii) Humoral immune response which involves the production of antibodies by B cells resulting in the
formation of antigen-antibody complexes that are subsequently removed.
The recognition of antigens (nonself molecules) is accomplished due to antigen processing and its
presentation by antigen presenting cells, to the T cells. Further, involvement of various cell surface
molecules and receptors, for e.g. MHC (Major Histocompatibility Complex) Class I & II molecules,
TCRs (T Cell Receptors), CD (Cluster of Differentiation) molecules, and secretion of a variety of
cytokines by some blood cells play specific roles in the execution of immune responses that ultimately
leads to the neutralization or destruction of pathogens or nonself molecules.
Many kinds of cells such as NK cells, NKT cells, dendritic cells, and macrophages of innate
immune system as well as CD4+ Th1 cells and cytotoxic T cells play a key role in the fight against
malignant cells as long as the immune system is capable of distinguishing the self from nonself. When
the self/nonself recognition ability of the immune system goes astray, it leads to the development of
autoimmune diseases. Due to a variety of reasons when certain cells of the immune system are not
produced or do not mature or fail to respond to the invading pathogens, it results in the development of
immunodeficiency diseases. Such individuals become the victims of bizarre opportunistic infections
from which they die sooner or later.
Phenomenal advances in the field of biology and in particular immunology have enabled us to
understand the complexities and intricacies of cellular and molecular interactions prevailing in the
immune system. This knowledge in turn has paved the way for discoveries and development of
commercially viable therapies and drugs for human health care. The emergence of many new pathogens
and drug resistant varieties have become a major threat and challenge for human survival. Consequently,
the quest for the discovery of drugs and development of measures to counter the pathogens in order to
reduce mortality and suffering continues…!!!
PART-I
Immunobiology
1. Innate and Adaptive Immunity

2. Organs and Tissues of the Immune System
3. Cells of the Immune System
4. Antigens
5. Immunoglobulins
6. B Cells
7. T Cells
8. Antigen Recognition
9. Complement
10. Cytokines
INNATE AND ADAPTIVE
1 IMMUNITY
LEARNING OBJECTIVES
After studying this chapter, the student will come to know
✓ What is immunity and different types of immunity
✓ The cells, molecules, and the mechanisms of innate immunity
✓ The types and mechanisms of adaptive immune response
✓ The interaction between innate and adaptive immunity and its importance
A variety of infectious microorganisms enter our body via the air we breathe, the water we drink, the
food we eat, the injuries that damage our skin or organs and yet, most of the times we remain resistant
to these infections since we have an immune system that provides protection. There are two ways by
which the immune system provides protection. They are innate or less specific immunity, which is the
first line of defense and the adaptive or specific immunity which is the second line of defense. These
two types of immunities operate by distinct mechanisms. At the same time, they also interact at different
levels to enhance the efficiency of the immune system. Immunity is defined as the state of protection of
an individual from an infectious agent or a foreign substance or a disease. In vertebrates, the immune
system has evolved remarkably to protect them from the pathogens or any kind of unwanted chemical
substances (antigens) before or after gaining entry. It consists of diverse organs and tissues that are
spread throughout the body. It is capable of generating enormous variety of cells and molecules. These
cells and molecules orchestrate or coordinate the complex process of identification, neutralization, or
destruction; as a consequence of which the microbe or foreign substance that comes in contact or that
has entered the body gets eliminated. Thus, the immune system can be compared to the military, its
various cells to soldiers, and the molecules to the weapons.
Usually antibodies are produced in an animal after it is exposed to an antigen (antigenic challenge).
The antibodies thus produced will neutralize the antigen by forming antigen-antibody complexes and
these complexes are later eliminated by different means. However, natural immunity may be present
in animals, which have not been immunized or infected with a pathogen, but still remain resistant. The
reason being, some antibodies are produced in individuals even in the absence of specific antigenic
10 Immunology
challenge. These antibodies are called normal antibodies or natural antibodies. They are found even
in germ-free animals fed on an antigen-free diet. Natural antibodies are immunoglobulin M (IgM)
isotype. They are normally present in the circulation of humans and other mammals that have never
been exposed earlier to those antigens to which they bind. These antibodies are in contrast to immune
antibodies, which are produced in response to an antigen. For example, isohemagglutinin (from
human plasma) is an antibody against the erythrocytes of other individuals. Natural antibodies are
present in horse against cholera, typhoid, and dysentery. Similarly, rabbits have natural antibodies
against pneumonia and dysentery. Natural antibodies against foreign erythrocytes are found in the
serum of various animal species. For example, swine has antibodies against erythrocytes of sheep, goat,
rabbit, and humans. Rabbit possess antibodies against the erythrocytes of guinea pig, horse, sheep, and
humans. While humans have in the serum, natural antibodies against rabbit, sheep, ox, horse, pigeon,
and guinea pig erythrocytes.
There are many direct factors such as nutritional status and age as well as indirect factors such as
personal hygiene, living conditions, and socioeconomic status that play a major role in host-parasite or
host-pathogen relationships and determine the ability of the host to resist the infection.
In general, higher the host is malnourished or undernourished, the greater will be its susceptibility to
the pathogens. This is especially evident in very young hosts. Experimental animals that are maintained
with low protein diet become susceptible to infections.
Generally very young or very old hosts are susceptible to infection. Babies are at a risk of infection
after the passive immunity (got from the mother) is depleted and before its own immune system becomes
functional. Infections of pathogenic strains of Escherichia coli and/or Pseudomonas aeruginosa that
cause diarrhea are frequent in infants under the age of 1 year. In very old individuals (above 65 years)
there will be a decline in the abilities of the immune system because the homeostatic functions of many
organs decrease and they are more susceptible to respiratory infections.
Stress also plays a significant role in the incidence of diseases. Experiments with rats and mice have
revealed that exertion, fatigue, dehydration, poor diet as well as drastic climatic changes and all sources
of physiological stress enhance the susceptibility of an individual to infectious diseases.
Further, the ability of an individual to defy an infection depends on certain indirect factors that vary
greatly from person to person and also from region to region. Generally, an individual becomes more
susceptible to infections if personal hygiene, socio-economic status, and living conditions are poor.
In higher vertebrates such as mammals, we can observe the prevalence of two types of immunity known
as innate immunity and adaptive immunity. The innate immunity or less specific immunity or natural
immunity or native immunity provides the first line of defense against pathogens or microorganisms
and/or foreign bodies that invade an individual by different means. These pathogens or microbes would
have to surpass one or more defense barriers such as anatomic, physiological, endocytic, phagocytic,
and inflammatory barriers in an individual. These barriers form an integral component of innate
immunity and they occur in an individual from the very early life and are effective against a variety of
pathogens or microorganisms and/or foreign bodies.
The adaptive immunity, also called acquired immunity is specific and represents the functional
immune system that is capable of specifically recognizing and selectively eliminating microorganisms
and/or foreign bodies. This type of immunity does not come into play unless a microorganism or a
foreign body enters an individual for the first time or subsequently. Adaptive immunity or acquired
11
immunity is characterized by specificity, recognition of self/nonself molecules and a unique property

of “memory”.
Cell mediated immune response and Humoral immune response

Immune responses could be of two types, viz., cell mediated immune response and humoral
immune response. The former mechanism includes direct participation of a variety of immune
cells that ensures eradication of cancer cells and microbe infected cells from the body. Whereas
the latter includes production of immunoglobulins into the serum and other body fluids that ensures
elimination of microbes or antigens.
In higher vertebrates such as mammals, a variety of effective defense mechanisms are present in an
individual from the very early stage of life. These mechanisms are capable of protecting the individual
from potentially harmful microorganisms and/or foreign bodies. Activation of such a defense mechanism
does not depend upon prior exposure of the body to any particular microorganism. The innate immune
mechanisms are effective against a wide range of potentially harmful infective agents.
The susceptibility of different species to pathogens differs. For example, human beings are not
affected by a large number of animal pathogens such as hog cholera, cattle plague, myxomatosis
etc. However, we remain susceptible to cholera, leprosy, syphilis, diphtheria etc. In some diseases,
it is difficult for a pathogen to infect the host; however once the pathogen gains entry, the disease
progression occurs rapidly due to the lack of resistance from the host. For example rabies, although
common to both man and dogs, it is not readily established since the virus does not easily penetrate
the healthy skin. However, once infected, the resistance mechanisms both in man and dog are unable
to overcome the disease. An interesting and exceptional feature of rabies is that the progression of the
disease can be prevented by administering vaccine after the bite of a rabid dog.
Rabies
Vaccination results in active immunization. The general rule is that vaccination has to be carried
out well before the infection occurs; so that the immune system of an individual will be able to
neutralize the pathogen or its products that causes the disease by producing antibodies against it.
An exception to this general rule is vaccination for rabies; where immunization can be initiated after
an individual is infected.
The susceptibility of different individuals of the same species to a particular pathogen also differs.
Variations in resistance to an infection between different strains of mice have been demonstrated. In
man, such differences among individuals to a certain extent are dependent upon the personal hygiene,
nutritional as well as socio-economic background. Sometimes genetic abnormalities are an advantage
to the individual in resisting infections. For example in humans, the genetic abnormality namely sickle
cell anemia is caused due to the presence of defective alleles (Hbs/Hbs) in homozygous condition.
Individuals with alleles for normal hemoglobin are susceptible to malaria. However, the heterozygous
individuals who carry one normal and one defective allele (HbA/Hbs), are resistant to infection by
Plasmodium falciparum and, hence, to malaria.
12 Immunology
What is Sickle Cell Anemia?

It is a genetic disease caused by the presence of defective alleles of hemoglobin gene in homozygous
condition (HbS/HbS) in place of normal alleles of hemoglobin (HbA/HbA).
Individuals with defective alleles contain red blood corpuscles (RBCs) which under low oxygen
tension (hypoxia) prevailing in veins, become sickle-shaped due to polymerization of hemoglobin.
The sickle-shaped erythrocytes get jammed in blood vessels and small capillaries and thus interfere
with proper flow of blood to different organs. Such a condition damages kidneys, muscles, joints,
brain, gastrointestinal tract, liver, and lungs.
The abnormal hemoglobin tends to produce crystals called ‘tectoids’ within the erythrocytes.
Tectoid formation results in the increased fragility of RBCs and anemia is caused due to the
destruction of erythrocytes leading to frequent illness, fatigue, poor physical development and
dilation of heart.
Individuals with normal haemoglobin are susceptible to infection by malarial parasite. Curiously,
the heterozygous individuals are resistant to malarial infection.
MECHANISMS OF INNATE IMMUNITY

1. Physical barriers and surface secretions
The intact skin and mucous membranes of
the body provide an effective protection Hair
against both nonpathogenic and
Pore of
pathogenic organisms. The epidermis of sweat gland
swea
the skin consists of four layers of cells.
Stratum
St
They are horny, granular, spinous, and EPIDERMIS RMIS
corneum
co
basal layers. The horny layer consists of
about 15 to 40 rows of dying cells (Fig. Sebaceous
eous
1.1). These cells are filled with a tough, gland
waterproof protein called keratin. This
DERMIS
MIS
layer is impervious to most microbes.
The skin has two kinds of glands viz., Hair
Hai bulb
sebaceous glands that secrete ‘sebum’ and
sweat glands that secrete ‘sweat’. These
secretions containing fatty acid, lactic Sweat
Swe gland
acid bring down the pH of the skin and
hence many kinds of bacteria and fungi
will be killed. Certain areas of the body, Artery Vein
such as soles of the feet do not have Fig. 1.1
sebaceous glands and thus are vulnerable
to infections. Thus sebum and sweat function as bactericidal and fungicidal agents. Further, a protein
namely dermicidin is produced in sweat glands. When it is transported on to epidermis, it undergoes
proteolysis to give rise to antimicrobial peptide that is effective against wide range of microbes at wide
range of pH and salt concentrations.
Many areas of the human body such as eyes, mouth, lungs, and digestive tract are not covered by
skin. These areas are constantly invaded by microbes and hence are more vulnerable for infection
13
by a variety of microorganisms. However, they do have some alternative defenses. For instance, the
damp surface (mucus) of the mucous membranes present in the respiratory tract and in the nose act as
a trapping mechanism and together with the action of cilia, sweep the foreign particulate material in
such a way that it passes into the throat, where it is swallowed. The acidic gastric juice in the stomach
destroys the microorganisms present in it. The microbes and foreign particles trapped within the mucus
are also removed by mechanical means such as coughing and sneezing.
Sneezing
When we inhale an irritant, it is sensed by the nerves
in the nostril. In response to which, the brain signals
the lungs to inhale deeply. The airways then close
to build air pressure in the lungs. This pressure
is suddenly released in a sneeze; thereby the
respiratory system gets rid of the irritant.
2. Physiologic barriers
The physiologic barriers that include temperature, pH, various soluble, and cell associated molecules
provide unfavorable conditions to many microorganisms. Many vertebrate species are resistant to
certain diseases basically because of their higher body temperatures (which of course is normal to that
species). For instance, chickens have higher body temperature (39.44°C/103 F) as compared to normal
human body temperature (37°C/98.6 F). Chickens are inherently resistant to anthrax because their
higher body temperature inhibits the growth of bacteria viz., Bacillus anthracis that causes anthrax.
The acidic nature of gastric secretion forms yet another barrier. Majority of the ingested microbes
are unable to survive in the stomach because of the acidic condition, the pH of which may vary from
2 to 4 depending on the type of meal. Many secreted body fluids contain bactericidal (an agent that
kills bacteria) components for example; Spermine and Zinc present in semen. The enzyme namely
lactoperoxidase present in the milk is a powerful oxidizing enzyme that can kill many kinds of bacteria.
Tears, urine, nasal secretions, cervical mucus, prostatic fluid and saliva contain a hydrolytic enzyme
namely lysozyme (muramidase). This enzyme cleaves the peptidoglycan layer of the bacterial cell
wall by hydrolyzing the bond between N-acetylglucosamine and N-acetylmuramic acid residues of
the peptidoglycan layer. A variety of bacteria are killed due to such damage caused to the cell wall.
A significant quantity of iron-binding protein lactoferrin (also called lactotransferrin) is present in
various secretory fluids such as milk, saliva, tears and nasal secretions. It is also released by activated
neutrophils and macrophages. Lactoferrin sequesters iron from the plasma; thereby reduces the
amount of free iron available to microbe and thereby limits the microbial proliferative ability. Mucous
membranes also produce enzyme lactoperoxidase that produces reactive oxygen form (superoxide)
which is toxic to many microorganisms. Further, animal tissues are found to contain a number of basic
proteins derived from damaged tissue and blood cells during the course of infection and inflammation.
This group includes basic proteins such as spermine and spermidine, which are capable of killing
tubercle bacilli and staphylococci.
14 Immunology
Bacterial cell wall

Both gram-positive and gram-negative bacteria have a cell wall surrounding the plasma membrane.
Their cell wall is made up of peptidoglycan. Gram negative bacteria have an additional outermost
layer made of lipopolysaccharide.
Rapid qualitative and quantitative changes occur in the host’s blood plasma during an acute infection.
These changes can bring down the virulence (ability to cause disease) of the pathogen. For instance, the
hosts are able to redistribute free iron in an attempt create a condition called ‘hypoferremia’. Conversely,
‘hyperferremia’ can cause infections by even the harmless organisms. When bacterial infection occurs,
macrophages are activated. As a consequence, many cytokines such as IL-1 (Interleukin-1), IL-6, IL-8
and TNF-a (Tumor Necrosis Factor-a) are released. These cytokines stimulate the liver to produce
many acute phase proteins. One such protein is C-reactive protein (CRP), the concentration of which in
plasma increases 1000 folds. CRP is a pentameric globular protein; which binds to phosphorylcholine
present on cell surface of many bacteria. Such an alteration of bacterial cell surface promotes
engulfment of bacteria by the phagocytes; and at the same time it can also activate the complement
proteins. Other acute phase proteins include mannose-binding lectin (MBL), surfactant proteins A (SP-A)
and D (SP-D). All these proteins act as opsonins since they promote phagocytosis by binding to the
bacterial cell surfaces on one side and on the other side, to the surface of phagocytes (Fig. 1.2). Further,
MBL activates alternative complement pathway. SP-A and SP-D are structurally related and are named
ACTIVATE
1
2
8 PHAGOCYTOSIS
Complement fragment/CRP ENHANCED

coated bacteria PHAGOCYTOSIS
7
Complement
fragments MACROPHAGES
IL-1, IL-6 3
Complement C-Reactive IL-8, TNF-a
activation Protein (CRP)
5
Mannose
binding lectin 4
Acute Phase
6 Proteins LIVER
Fig. 1.2
15
collectins (also known as defense collagens). They bind to cellular debris and dying cells and these
complexes later are engulfed by phagocytes.
Fever is caused due to the disturbances in hypothalamic thermoregulatory activity. There will
be an increase in the thermal “set point”. Adult humans have an oral temperature of 37°C or rectal
temperature of 37.5°C. Any increase in this set point results in fever. Several components of the
infecting organism such as (a) Bacterial endotoxins (b) N-acetylglucosamine-N-acetylmuramic acid
polymer of gram-negative bacteria (c) Derived portion of the peptidoglycan cell wall of both gram-
positive and gram-negative bacteria (d) Soluble enterotoxin of staphylococci (e) Erythrogenic toxin of
group A streptococci; will be able to trigger the fever. These components are called pyrogens or more
specifically, they are called exogenous pyrogens.
Certain microbes need free iron at a crucial concentration for the synthesis of their toxins and for
their proliferation; in the absence of which, their growth is retarded. Fever causes reduction of free
plasma iron. The fever also augments and mobilizes host’s macrophages, which in turn neutralize/
destroy pathogen by more than one mechanism. Certain cytokines such as IL-1, IL-6, TNF-a that are
produced by host macrophages act as endogenous pyrogens. IL-1 also causes proliferation, maturation
and activation of both T and B lymphocytes; which in turn augment the immune responses of the host.
Many microbes are unable to withstand higher body temperatures caused during fever and hence fail
to establish themselves in the host.
3. Other chemical barriers

(a) It is a high molecular weight glycoprotein found in a soluble form in plasma and other
body fluids. It is produced by the liver and forms a major blood component. It can bind to the cell
wall components of certain bacteria such as Staphylococcus aureus and Streptococci groups A, C and
G. These interactions opsonize phagocytes and thus promote the nonspecific elimination of certain
bacteria from the body. Further, fibronectin also binds to the receptors present on certain epithelial
cells. Such a binding will block the receptors and thereby prevents the bacterial infection.
Activated macrophages produce defensins. These are a group of antimicrobial
peptides and are cysteine rich cationic peptides made up of 29-35 amino acids. Defensins can kill
Staphylococcus aureus, Streptococcus penumoniae, Escherichia coli, Pseudomonas aeruginosa and
Haemophilus influenzae. b-Lysin is another cationic polypeptide which is released from platelets.
It kills some gram-positive bacteria by damaging their plasma membranes. While histatin, that is
found in human saliva has antifungal activity. In mammals, peptides with antibacterial activity, such
as cathelicidins are produced. These peptides are expressed in neutrophils and on epithelial surfaces
and are believed to provide a first line of defense against infection by acting as ‘natural antibiotics’.
Cathelicidins have been shown to be an important native component of the innate host defense in mice
and they also provide protection against necrotic skin infection caused by Group A Streptococcus.
Other cationic polypeptides include leukins, plakins and phagocytin. The prostate gland in men secretes
a zinc-containing polypeptide namely prostatic antibacterial factor.
They are a family of glycoproteins synthesized and secreted by host cells. Viral
infection, double stranded RNA, endotoxins, mitogenic agents, antigenic stimuli, intracellular parasites
such as Listeria monocytogenes, Chlamydiae, Rickettsias and Protozoans induce interferon production.
Virally infected host cells synthesize and secrete interferons (IFNs). These secreted IFNs bind to
the interferon receptors on the neighboring uninfected cells. Following which, the uninfected cells
start synthesizing antiviral proteins. One of these antiviral protein thus synthesized is an active
endoribonuclease, and thus is capable of degrading the viral genome. Another antiviral protein that
is synthesized during this period is an active protein kinase. This protein kinase phosphorylates and
16 Immunology
inactivates the initiation factor eIF-2 of the host cells which is needed for viral protein synthesis.
There are five major classes of interferons. Table 1.1 shows some interferons and secreting cells/
tissues. Interferon-a (IFN-a) which consists of a family of 20 different molecules, are secreted by
virus infected leucocytes. IFN-b is secreted by virus infected fibroblasts; whereas IFN-g is secreted by
antigen stimulated T cells. Placenta secretes two types of interferons viz., IFN-w and IFN-t.
Table 1.1
Interferon Secreting Cells/Tissue
IFN-a Leucocytes
IFN-b Virus infected fibroblasts
IFN-g Antigen stimulated T-cells
IFN-w Placenta
IFN-t Placenta
4. Microbial antagonism
Microbial antagonism is nothing but the property of microbes, in which a microorganism will be able
to kill or injure, or inhibit the growth of different microorganisms. The skin and mucous membranes
that are constantly in contact with organisms in the environment become readily colonized by various
microbial species. The microorganisms that are regularly found at any region in the body is referred
to as normal microflora. The growth and establishment of many potentially pathogenic bacteria and
fungi at these sites are suppressed by competition with normal microflora for essential nutrients or
due to the production of inhibitory substances namely bacteriocins by the normal microflora. Table
1.2 shows normal microflora of humans. Bacteriocins are toxic proteins secreted by Gram–negative
bacterial flora in our body. For example, E. coli synthesizes bacteriocins called colicins. These toxic
proteins inhibit the growth of similar or closely related bacterial strains. Other bacteriocins include
halocin, mutacin, nicin, sakacin, vibriocin etc. Thus, bacteriocins are made by nonpathogenic bacteria
that normally colonize the human body and are of interest in medicine. The Gram-positive bacterial
flora produces bacteriocin like peptides. The loss of these bacteria due to the use of antibiotics
may result in opportunistic infections by pathogenic microorganisms. For example, in humans, the
vaginal epithelium of adult female produces glycogen. The normal microflora of vaginal region viz.,
Table 1.2
Bacterium Skin Conjunctiva Nose Pharynx Mouth Lower Anterior Vagina
intestine urethra
Staphylococcus ++ + ++ ++ ++ + ++ ++
epidermidis
Staphylococcus + +/– + + + ++ +/– +
aureus
Lactobacillus sp. + ++ ++ ++
Escherichia coli +/– +/– +/– + ++ + +
++ = About 100%; + = About 25%; +/– = Rare < 5%

17
Lactobacillus acidophilus produces lactic acid by fermenting this glycogen. As a consequence of the
activity of normal microflora, the pH of the vagina and cervix ranges from 4.4 to 4.6. This acidic
pH can prevent the invasion and colonization of this region by potential pathogens. These protective
commensals are disturbed when antibiotics are administered during any other illness. Under such
circumstances, the women become more susceptible to opportunistic infections by pathogens such as
Candida and Clostridium difficile. Further, it is also known that corynebacteria on the skin produce
fatty acids. These fatty acids inhibit the colonization of pathogenic bacteria.
5. Endocytic and phagocytic barriers

Ingestion of extracellular material or macromolecules or microbes through either endocytosis or
phagocytosis is another innate defense mechanism. The microorganisms or inert particles such as
colloidal carbon entering the tissue fluids or blood stream are very rapidly engulfed by neutrophils and
macrophages.
The neutrophils have multilobed nucleus with varying morphology and thus are also
called polymorphonuclear leucocytes (PMN) (Fig 1.3). They are also called microphages since they are
smaller when compared to another type of phagocyte viz., macrophage.
Fig. 1.3
They are larger than neutrophils. Unlike the neutrophils, macrophages have single,
large nucleus. Hence they are also called mononuclear phagocytes (Fig. 1.3). They are distributed
throughout the body, which are both circulating in blood and fixed to tissues. These are the cells of the
reticuloendothelial system or RES.
The macromolecules that are present in the extracellular tissue fluid are engulfed by cells by
endocytosis, during which small regions of the plasma membrane invaginate or fold inward forming
endocytic vesicles. The diameter of the vesicles formed is approximately 0.1 mm. Endocytosis may
occur by one of the two methods: (i) Pinocytosis and (ii) Receptor mediated endocytosis (Fig. 1.4).
In pinocytosis, the macromolecules are phagocytosed by the way of nonspecific membrane
invagination. Whereas in case of receptor mediated endocytosis, the macromolecules are selectively
phagocytosed after they bind to specific membrane receptors. Such phagocytosed vesicles are called
endocytic vesicles. These endocytic vesicles fuse with each other and are delivered to endosomes. The
endosomes are acidic compartments present within the cells and they serve a sorting function. Their
acid environment causes dissociation of the receptor from its ligand. The receptor is recycled to the
plasma membrane of the cell, while the remaining macromolecules contained within the endosome
are passed along a different pathway to fuse with the primary lysosomes. The primary lysosomes
contain a large number of degradative enzymes such as acid phosphatase, acid RNase, acid DNase,
18 Immunology
Extracellular fluid Extracellular fluid
Receptor
Vesicle Coated pit
Plasma
membrane
Cytoplasm
Coated vesicle
Fig. 1.4
receptor mediated endocytosis (right)
b-glucuronidase, lipase, aryl sulfatase, cathepsins, peroxidase etc. The endosomes upon its fusion
with primary lysosomes become secondary lysosomes. Within the secondary lysosomes, the ingested
macromolecules are digested into small breakdown products (peptides, nucleotides, sugars) in the
endosomal processing pathway.
The ingestion of particulate material, including whole
pathogenic microorganism occurs by phagocytosis (Fig. Solid particle
1.5). Phagocytosis differs from endocytosis in many
Pseudopodia
respects. (a) In phagocytosis, the plasma membrane of the
phagocytic cell expands around particulate material to form
large vesicles called phagosomes. (b) The phagosomes are
10-20 times larger in size than endocytic vesicles. (c) The
expansion of plasma membrane in phagocytosis requires the
participation of cytoskeletal structure called microfilaments
(not in endocytosis). (d) Only specialized cells such as blood Plasma
membrane
monocytes, neutrophils and tissue macrophages are capable of
phagocytosis whereas virtually all cells carry out endocytosis.
The phagocytes have several mechanisms to deal with the
ingested microbe. Neutrophils can secrete transferin, which Phagosome
chelates the iron and prevents some bacteria from obtaining
this very important nutrient. While the macrophages are
Fig 1.5
capable of secreting Reactive Oxygen Intermediates (ROIs)
into the phagosomes and these ROIs are toxic to some
bacteria. Finally, the cytoplasmic granules and lysosomes fuse with phagosomes pouring the contents
of lysosomes into the phagosomes leading to digestion of the ingested material.
19
6. Inflammation
It is nonspecific and an important defense reaction.
Inflammation (Latin: inflammatio – to set on fire) is the body’s
reaction to the following:
(a) Invasion by an infectious agent
(b) Antigenic challenge or
(c) Even just a physical damage
As early as 1600 B.C., we find the description of classic
features of the inflammatory response in the Egyptian
writings. In the first century A.D., the Roman physician Celsus
described the “four cardinal signs of inflammation” as rubor
(redness), tumor (swelling), calor (heat) and dolor (pain). The
three major events that occur during inflammatory response
causing the cardinal signs include the following:
(i) Vasodilation (increase in the diameter of blood vessels)
of nearby capillaries; leading to an increased blood
supply to the infected area. Simultaneously, there will be
a vasoconstriction (decrease in the diameter of blood vessels) of the vessels that carry blood away
from the affected area. These two processes together cause the redness (rubor) and an increase in
tissue temperature (calor) of the affected area.
(ii) Increase in capillary permeability; caused by the retraction of the endothelial cells is another
major event. Such an increased permeability allows the escape of larger molecules (larger than
the molecules that normally escape) from the capillaries. As a result of this, antibody, complement
and other plasma enzyme systems reach the inflammatory site (site of infection/site of injury),
leading to the accumulation of fluid or exudates, causing swelling (tumor) and pain (dolor) of the
affected area.
(iii) Migration or Influx of leucocytes; wherein initially neutrophils and 5-6 hours later macrophages
and lymphocytes from the blood migrate out of capillaries into the surrounding tissues to carry
out their function.
The vascular endothelium serves as “gate keeper” that regulates the movement of blood borne
molecules and leukocytes in to the tissues. During inflammatory response, the cells from the blood
migrate into the tissues or the affected region. In this process, the adherence of leucocytes to the
endothelium of blood capillaries surrounding the affected tissues is the first step in the process of
migration of cells (Fig. 1.6). Such an adherence occurs due to the interaction of receptors viz., very
Rolling Margination
Extravasation
Endothalium
Fig. 1.6
tissues during inflammatory response
20 Immunology
late antigen-4 (VLA-4), P-selectin glycoprotein ligand-1 (PSGL-1) and leucocyte function associated
antigen-1 (LFA-1) that are present on the surface of leucocytes with the corresponding ligands viz.,
vascular cell adhesion molecule-1 (VCAM-1), P-selectin and intercellular adhesion molecule-1
(ICAM-1) on the activated endothelial cells respectively (Fig. 1.7). This process is called pavementing
or margination. After margination, the phagocytes insert pseudopodia between the endothelial cells
and dissolve the basement membrane of the blood capillary. They then emigrate between the capillary
endothelial cells into the tissue. This process is called diapedesis or extravasation. Once they are in the
tissues, the movement of leucocytes towards the site of infection is directed by chemicals (chemotaxis),
during which the phagocytes will actively migrate towards the source of chemotactic molecules or
chemotactic peptides. Tissue damage results in the generation of C3a and C5a complement fragments.
These fragments attract both neutrophils (microphage) and monocytes (macrophage). The moment
different phagocytes reach the site of infection/injury they begin to engulf bacteria (Fig. 1.7). Further,
the phagocytes also release lytic enzymes, which can damage surrounding healthy cells/tissue. The
accumulation of dead cells, digested material and fluid forms a substance called pus. The C3a and C5a
bind to local mast cells and cause the release of mediators (Histamine, Leukotrienes, Prostaglandins).
These mediators cause vasodilation, smooth muscle contraction and increased vascular permeability.
Similarly, endothelial damage induce plasma enzyme mediators (Bradykinin, fibrinopeptides) that also
bring about vasodilation and increased vascular permeability.
BLOOD TISSUES
Basement
membrane
Monocyte
Activation of
C3a complement
ca l
C5a la ssi
VLA-4 Mediators
o rc
VCAM-1
hw v e
Mast cell
s
ti
ay
Tissue
rna
Chemotaxis damage
Alte
Neutrophil
pat
Chemot Microbes
axis
C3a, C5a
IL-8 C5b67
Chemokines
PSGL-1 Endothelial
IL-1, IL-6, TNF-a damage
P-selectin
Prostaglandins
Lymphocyte Leukotrienes
Activated
macrophage
Extra vasation
LFA-1
ICAM-1
Fig. 1.7
acute inflammatory response
21
There are two types of inflammatory responses. They are (a) Acute inflammation which is rapid and
short lived, which may last for two weeks or more (b) Chronic inflammation is slow and long lived. The
former occurs due to infection or tissue damage or entry of an antigen; while the latter is caused due to
the persistence of infections as in mycobacterial infections that cause tuberculosis and leprosy. These
bacteria can resist phagocytosis and intracellular killing and thus can survive within macrophages. By
acute inflammatory response, the infection is eliminated. In case of chronic inflammatory response,
there will be an enhanced infiltration of lymphocytes and macrophages and the body attempts to wall off
and seclude the affected site by forming granuloma, as seen in case of bacterial infections (listeriosis,
brucellosis), fungal infections (histoplasmosis, coccidomycosis), helminth infection (schistosomiasis),
protozoan infection (leishmaniasis) and large antigen-antibody complexes (rheumatoid arthritis).
The adaptive immunity forms the second line of defense. It is the immunity, which is acquired and is
specific to a particular pathogen/antigen. The adaptive immunity may be of active, passive, or adoptive
type (Fig. 1.8).
Naturally acquired
(Natural infection)
ACTIVE
Artificially acquired
ADAPTIVE IMMUNITY
(Vaccination)
Naturally acquired
(Mother's antibodies)
PASSIVE
Artificially acquired
(Antibodies from other sources)
ADOPTIVE
Fig. 1.8
This form of immunity is acquired due to the exposure of an individual to a pathogen or an immunogenic
substance by natural or artificial means. Such an exposure results in the stimulation of immune system
to produce antibodies that are specifically directed against the inducing pathogen or immunogen.
Recognition of pathogen or immunogen by the immune system is followed by immunological memory;
that is, when the same individual encounters the same pathogen or immunogen subsequently, there will
be a rapid and heightened state of immune response again, ultimately resulting in the production of
specific antibodies to neutralize the pathogen or immunogen.
1. Naturally acquired
Natural stimulation of antibody producing mechanism occurs when we suffer and recover from a disease.
This will usually result in the long-term immunity and prevent incidence of the same disease again.
22 Immunology
This kind of immunity is also developed

whenever subclinical or undetected
infections occur. The immunity thus
acquired is called naturally acquired
active specific immunity or naturally
acquired specific immunity.
2. Artificially acquired
The specific immunity could also be
acquired due to the stimulation of antibody
producing mechanisms artificially, by
deliberately introducing a pathogen or
some of their components or their products
which cause the disease (Fig. 1.9). For
artificial immunization, sublethal doses Fig. 1.9
of attenuated (weakened) organisms or
their products are employed. The pathogens can be attenuated or weakened by aging the cultures, or
by exposing the cultures to high temperatures or also by growing the pathogens in an unnatural host
(see Chapter 14). These procedures ensure a reduction or loss of virulence of the pathogens. Such
organisms that have lost virulence, but retain immunogenic property, are used for inducing specific
immunity. The preferred method of stimulating antibody response against many diseases is to use the
killed microorganisms. Many methods are employed to kill the microbes. Commonly, the microbes are
killed by treating the pathogens with acetone, formaldehyde, phenol, heat etc. Whenever toxins of the
pathogens have to be used for immunization, treatment of toxins with formaldehyde will convert most
of these to nontoxic antigenic toxoids that can be used for artificial immunization. These preparations
are called vaccines and the procedure of using them to induce immunity is called vaccination. The
immunity thus acquired is called Artificially acquired active specific immunity or artificially
acquired specific immunity. Some commonly used vaccines to induce resistance against diseases are
listed in Table 1.3.
Table 1.3
Vaccine Live Killed
Bacterial BCG (for tuberculosis) TAB (for enteric fever), cholera
Viral Oral poliomyelitis, measles, mumps Salk vaccine (for poliomyelitis), rabies
Bacterial products Toxoids: Diphtheria, Tetanus
Capsular polysaccharides: Meningococcus, Pneumococcus, Haemophilus
Surface antigen: Hepatitis B Virus
This type of immunity develops following the transfer of antibodies that have been made in another
individual. Such an immunity usually lasts only for a short period since these antibodies are catabolized
like any other normal globulin and thus disappear from circulation in the recipient after a short period.
23
1. Naturally acquired
During the first few months of an animal’s life or
human life, many diseases do not affect; which
otherwise ordinarily affect the animal or man in the
later part of life. This kind of resistance to many
diseases can be attributed to antibodies, which have
been transferred from the mother to the infant. Such
a transfer of antibodies to the growing embryo occurs
in the mother’s womb through the placenta and this
process is called transplacental passage. Passage of
antibodies through placenta has been demonstrated
in several animals. In both humans and animals such
as pig and cattle where placental and fetal circulatory Fig. 1.10
systems are separated by more than one layer of cells,
the passage of antibodies (mother’s IgA and IgG) also occur shortly after birth when the neonate feeds
on the first milk of the mother called colostrum (Fig. 1.10). The neonate continues to get the mother’s
antibodies in this way in the neonatal life. The antibodies that are obtained by the newborn through
colostrum are absorbed in the gastrointestinal tract of the newborn. These antibodies can neutralize
pathogenic microbes that attempt to colonize the infant’s gut. Further, IgG is taken up specifically from
the gut into the blood of the neonate and this transport is mediated by a receptor. The immunity thus
acquired by passive manner, is lost rapidly and then specific immunity will be acquired in an active
manner by individual’s own immunologic mechanisms during the course of life. Naturally acquired
passive immunity is quite important, since this mechanism protects the newborn during the period
when the immune capacities of the new born are yet to be developed.
2. Artificially acquired
This type of immunity includes the administration of antibody containing sera from the artificially
immunized animals (Fig. 1.11) or from the humans who have contracted and recovered from a disease.
Before the advent of antibiotics, immunization of an individual by this method was a common practice
in the treatment of diseases such as pneumonia.
Snake bite
Artificially immunized
animals
OR Antibodies Recipient
Naturally actively
immunized individuals
Fig. 1.11
24 Immunology
Antibodies that are raised in some other hosts are administered to prevent the severity of the disease.
Antibodies of human origin and animal origin are used for this purpose. The antibodies of human origin
(usually called immune serum globulin or gamma globulin) are preferred over those of animal origin
because of high incidence of adverse reaction to animal sera. In addition, the antibodies of human
origin provide protection for longer periods as compared to the antibodies of animal origin. The choice
for passive immunization is inevitable when the vaccines for active immunization are not available
or when the use of vaccines for active immunization is not advocated or if the recipient is primarily
immunodeficient whose immune system fails to respond to an antigen or in case of immunosuppressed
individuals.
When antibodies of animal origin are used, there will be a relatively high risk of developing serum
sickness. Hence, the use of human Ig is recommended wherever possible. During the preparations
of human Ig, the plasma which is positive for hepatitis B, hepatitis C or human immunodeficiency
virus (HIV) is discarded. If the use of antibodies of animal origin is inevitable, it has to be tested for
hypersensitivity before administering the same. Usually phenol is used as preservative for antibody
preparations. In some instances, thimerosal is also used.
Some reactions such as erythema and stiffness of local muscles occur commonly at the site of
injection. The discomforts caused by these reactions may persist for several hours. Occasionally mild
fever or malaise may occur. Rarely some side effects such as flushing, headache, chills and nausea also
occur. Further, anaphylactic reactions may occur rarely when repeated administration of the antibodies
is made. In 1998, the first monoclonal antibody named Palivizumab was licensed for its use, to prevent
an infectious disease namely respiratory syncytial virus in high-risk infants.
The artificially acquired passive immunity poses limitations because of the following reasons:
(a) The duration of immunity is short. It depends on the quantity of antibody injected and its life in
the circulation of the recipient.
(b) The antiserum has to be given very shortly after the exposure to the disease. It will not be helpful
if the antiserum is given after the disease has progressed/developed fully and damage has been
done.
(c) The antiserum has to be given in as large amounts as possible. However, when the antiserum
obtained from another animal/person is administered in large amounts, there is also a danger of
developing serum sickness by the recipient; which may result in severe side effects or even death.
However, in many instances the passive immunization is practiced (Table 1.4).
Table 1.4
Disease/condition Source of antibodies
Black widow spider bite Horse antivenin
Botulism Horse antitoxin
Diphtheria Horse antitoxin
Hepatitis A and B Pooled human immune gamma globulin
Measles Pooled human immune gamma globulin
Rabies Pooled human immune gamma globulin
Snake bite Horse antivenin
Tetanus Pooled human immune gamma globulin OR Horse antitoxin
25
What is Serum sickness?

It is the sickness caused by the injection of large doses of foreign serum or serum proteins. The
sickness is characterized by fever, joint pains and nephritis caused due to the formation of immune
complexes of injected antibodies and the proteins present.
A special type of immunity is acquired by the recipient due to the injection or introduction of
immunologically competent cells (Fig. 1.12). Instead of whole of the lymphocytes, an extract of
immunologically competent lymphocytes known as “transfer factor” can be used for this purpose.
This is being attempted in the therapy of some types of diseases such as lepromatous leprosy. Tissue
typing must be done for checking the compatibility before transferring immunologically competent
lymphocytes into the recipient to prevent incompatibility. Thus, it is a type of acquired immunity in
which immunity is transferred from one individual to another by the transfer of lymphocytes that are
immunologically active. Adoptive immunity is regarded as an intermediate between active and passive
immunity. It is active in the sense that it is based on the presence of actively functioning cells, which
have been stimulated by an antigen; now growing and functioning in a host after being transferred from
a donor. It is passive in the sense that the immunity is not produced in the host and is not the outcome
of its own active response to immunization.
Immunologically
competent
Donor
Lymphocytes
Recipient
Fig. 1.12
The innate immune system provides an immediate defense against infection. It is an additional system
for adaptive immune response. Virtually, there is a constant interaction between the cells and/or the
molecules concerned with the innate and adaptive immunity. It is possible that the innate immune
system plays an important role of reducing the quantum of pathogens during infection, thus reducing
the “burden” on adaptive immune response.
In the event of invasion by pathogens, the innate immune system is activated first to render initial
attack against the pathogens. Simultaneously, certain antigen presenting cells residing in different entry
points of pathogens are also activated. For instance, the skin in the adult humans has a surface area
of approximately 20 sq.ft.; infection could also occur through skin when it is damaged due to an
insect bite or an injury. The areas that are without skin (epithelial surfaces) measure about 4000 sq.ft.
Since most of these areas are exposed to the environment, the infection usually occurs due to the
26 Immunology
entry of pathogens in to our body through Virus

mucosal surfaces. One of the important
cell types associated with the innate
immunity include dendritic cells. These Bacteria Attention Nucleic acid
are antigen presenting cells residing in
peripheral tissues such as mucosa, skin
and internal organs and also in blood and
lymphoid tissues. They are capable of
discriminating between self-molecules
and nonself-molecules or pathogens.
Whether it is mucosal or cutaneous
or systemic infections, the dendritic
cells residing in the entry points of the
pathogens have the ability to hold and
Plasma membrane
eliminate these pathogens. These cells
after coming in contact with the antigen/pathogen get activated and migrate from the infected tissue to
the regional lymph nodes where they in turn activate T cells by presenting the antigens. Consequently,
the adaptive immune system is activated causing the production of antibodies that specifically binds to
the antigen/pathogen.
The innate immunity recognizes certain molecules that are present on microorganisms. These
molecules are called pathogen-associated molecular patterns (PAMPs). The PAMPs are sometimes
referred to as microbe-associated molecular patterns (MAMPs). Whenever cells are infected, injured,
stressed, or transformed; they display unique molecules on their surfaces. These molecules are called
damage-associated molecular patterns (DAMPs). Certain PAMPs, DAMPs and their sources are
listed in Table 1.5.
Table 1.5
PAMPs Source
Lipopolysaccharide, porins Gram-negative bacterial cell wall
Lipoproteins and lipopeptides Bacteria
Peptidoglycan, lipoteichoic acid Gram-positive bacterial cell wall
Lipoarabinomannan Acid-fast bacterial cell wall
Flagellin Bacterial flagella
Pilin Bacterial pili
Phosphorylcholine Microbial membranes
N-formylmethionine Bacterial proteins
DAMPs Source
Heat shock proteins Stressed, injured, infected, or transformed host cells
Altered membrane phospholipids Stressed, injured, infected, or transformed host cells
Different body cells have receptors called pattern-recognition receptors (PRRs) that recognize
PAMPs and DAMPs. Various body cells such as macrophages, endothelial cells, mucosal epithelial cells,
dendritic cells and lymphocytes typically have PRRs. Toll-like receptors (TLRs), the transmembrane
27
proteins present on the surface or on the endosomes of antigen presenting cells (such as dendritic cells)
were the first PRRs to be discovered and implicated in the innate immunity. The TLRs can recognize
a variety of components of bacteria and viruses that can be categorized into lipid, protein and nucleic
acid. These evolutionarily conserved PRRs are found to increase the antigenic response. They are also
found to form a link between the innate and the adaptive immunity. Altogether, the innate immune
system in humans is believed to recognize about 103 molecular patterns.
Following the entry of pathogen and/or an antigen several mechanisms, molecules and coordinated
sequence of events of innate and of adaptive immunity come into play (Table 1.6) almost simultaneously
to neutralize or eliminate the pathogen/antigen and to ensure the health of the individual.
Table 1.6
Feature Innate immunity Adaptive immunity
Type of response Antigen independent, Cell mediated Antigen dependent, Humoral

Time needed for response In most instances, immediate (Rapid) Accompanied by lag period between
exposure and maximal response
(Slow to start)
Specificity Not antigen specific Antigen specific
Prior exposure to antigen Not required Required
Physical barriers Skin, Mucous membranes —
Physiologic barriers pH, Temperature —
Cells Microphages, Macrophages, Natural T cells, B cells
Killer cells, Dendritic cells
Proteins/Enzymes Lysozyme, Defensins, Dermicidin, Antibodies
Lactoferrin, Lactoperoxidase, Spermine, (Immunoglobulins)
Spermidine, Fibronectin, Histatin,
Interferons, Bacteriocins
Immunological memory Absent Present
SUMMARY
✥
✥
28 Immunology
SHORT ANSWER QUESTIONS

1. List out any four kinds of defensive barriers that prevent the invasion of a pathogen.
2. List out at least four factors that enable the host to resist infection.
3. What are exogenous pyrogens? Give examples.
4. Explain how skin provides protection against microorganisms?
5. List out at least four physiological barriers that provide hostile conditions to many microorganisms.
6. Name four body secretions that contain lysozyme.
7. Explain how lactoferrin limits the microbial proliferation?
8. What are cationic peptides? Give examples.
9. What are interferons? List at least four them and their sources.
10. List out at least four defensive proteins/enzymes.
11. List out at least two differences between endocytosis and phagocytosis.
12. Which are the cardinal signs of inflammation?
13. How ‘rubor’ and ‘calor’ are caused?
14. How swelling is caused at the site of tissue injury?
15. How chronic inflammation differs from acute inflammation?
16. What is granuloma? Give at least two examples.
17. Which are the three types of adaptive immune response?
18. List two bacterial and two viral vaccines that are commonly used.
19. Which are the bacterial products used for making vaccines?
20. How does the mother’s IgA and IgG antibodies are transferred into the child in humans?
21. Artificially acquired passive immunity is short lived. Why?
22. List four instances of passive immunization.
23. Explain how adoptive immunity is an intermediate between active and passive immunity?
24. What are TLRs? Name two TLRs and their microbial ligands.
25. What are PAMPs? Name two PAMPs and their sources.
26. List out the cells that have PRRs to recognize PAMPs.
29
ESSAY TYPE QUESTIONS

27. What is innate immunity? Write an account on physical and physiologic barriers of innate
immunity.
28. Explain how our body is defended against infection by means of endocytic barriers, phagocytic
barriers and microbial antagonism?
29. Describe cardinal features and the mechanism of inflammatory response.
30. Give an account of specific acquired immunity. Add a note on the interaction between the innate
and the adaptive immunity.
Another random document with
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guide a tool. The slide-rest, while it had been invented, had not been
put into practical form or come into general use. There were a few
rude drilling and boring machines, but no planing machines, either
for metal or wood. The tool equipment of the machinist, or
“millwright,” as he was called, consisted chiefly of a hammer, chisel
and file. The only measuring devices were calipers and a wooden
rule, with occasional reference perhaps to “the thickness of an old
shilling,” as above. Hand forging was probably as good as or better
than that of today. Foundry work had come up to at least the needs
of the time. But the appliances for cutting metal were little better than
those of the Middle Ages.
Such was the mechanical equipment in 1775; practically what it
had been for generations. By 1850 it was substantially that of today.
In fact, most of this change came in one generation, from about 1800
to 1840. Since that time there have been many improvements and
refinements, but the general principles remain little changed. With so
wonderful a transformation in so short a time, several questions arise
almost inevitably: Where did this development take place, who
brought it about, and why was it so rapid?
The first question is fairly simple. England and America produced
the modern machine tool. In the period mentioned, England
developed most of the general machine tools of the present day; the
boring machine, engine lathe, planer, shaper, the steam hammer and
standard taps and dies. Somewhat later, but partially coincident with
this, America developed the special machine tool, the drop hammer,
automatic lathes, the widespread commercial use of limit gauges,
and the interchangeable system of manufacture.
In a generalization such as this, the broad lines of influence must
be given the chief consideration. Some of the most valuable general
tools, such as the universal miller and the grinder, and parts of the
standard tools, as the apron in the lathe, are of American origin. But,
with all allowances, most of the general machine tools were
developed in England and spread from there throughout the world
either by utilization of their design or by actual sale. On the other
hand, the interchangeable system of manufacture, in a well-
developed form, was in operation in England in the manufacture of
ships’ blocks at Portsmouth shortly after 1800; and yet this block-
making machinery had been running for two generations with little or
no influence on the general manufacturing of the country, when
England, in 1855, imported from America the Enfield gun machinery
and adopted what they themselves styled the “American”
interchangeable system of gun making.[7]
[7] See page 139.
The second question as to who brought this change about is not

so simple. It is not easy to assign the credit of an invention. Mere
priority of suggestion or even of experiment seems hardly sufficient.
Nearly every great improvement has been invented independently by
a number of men, sometimes almost simultaneously, but often in
widely separated times and places. Of these, the man who made it a
success is usually found to have united to the element of invention a
superior mechanical skill. He is the one who first embodied the
invention in such proportions and mechanical design as to make it
commercially available, and from him its permanent influence
spreads. The chief credit is due to him because he impressed it on
the world. Some examples may illustrate this point.
Leonardo da Vinci in the fifteenth century anticipated many of the
modern tools.[8] His sketches are fascinating and show a wonderful
and fertile ingenuity, but, while we wonder, we smile at their
proportions. Had not a later generation of mechanics arisen to re-
invent and re-design these tools, mechanical engineering would still
be as unknown as when he died.
[8] American Machinist, Vol. 32, Part 2, pp. 821 and 868.
Take the slide-rest. It is clearly shown in the French encyclopedia

of 1772, see Fig. 3, and even in an edition of 1717. Bramah,
Bentham and Brunel, in England, and Sylvanus Brown,[9] in America,
are all said to have invented it. David Wilkinson, of Pawtucket, R. I.,
was granted a patent for it in 1798.[10] But the invention has been,
and will always be, credited to Henry Maudslay, of London. It is right
that it should be, for he first designed and built it properly, developed
its possibilities, and made it generally useful. The modern slide-rest
is a lineal descendant from his.
[9] Goodrich: “History of Pawtucket,” pp. 47-48. Pawtucket, 1876.
[10] Ibid., p. 51.
Blanchard was by no means the first to turn irregular forms on a

lathe. The old French rose engine lathe, shown in Fig. 4, embodied
the idea, but Blanchard accomplished it in a way more mechanical,
of a far wider range of usefulness, and his machine is in general use
to this day.
Figure 3. French Slide-Rest, 1772
Figure 4. French Lathe for Turning Ovals, 1772
The spindle swings sidewise under the influence of the two cams which bear
against the upright stops
JOSEPH BRAMAH Sir SAMUEL Sir MARC I.
1748-1814 BENTHAM BRUNEL
Invented Lock, Hydraulic 1757-1831 1769-1849
press, 4-way cock, and 44 NEW MACHINES.
wood working machinery. BLOCK M’CHRY-1800-08
HENRY MAUDSLAY
1771-1831
Slide rest for metal work, Block machinery, Flour,
Sawmill and Mint mach’ry, Punches, Mill and Marine
Steam Engines, Fine screw cutting. Laid basis for
Lathe, Planer and Slotter
JOSEPH CLEMENT
1779-1844
Slide Lathe, Planer 1820 and 1824
Manufactured Taps and Dies Standard
Screw Threads
MATT. JAMES RICH’D. JOSEPH JAMES
MURRAY FOX ROBERTS WHITWORTH NASMYTH
1803-87 1808-90
Engines D- Index Versatile Std. Screw Index
Valve Cutting of Inventor, Threads Milling
Planer Gears Planer Foremost tool Shaper
Lathes, builder of the Steam
Planer 19th Century Hammer
Am. Machinist
Figure 5. Genealogy of the Early English Tool Builders
To the third question as to why this development when once begun

should have been so rapid, there are probably two answers. First, an
entirely new demand for accurate tools arose during these years,
springing from the inventions of Arkwright, Whitney, Watt, Fulton,
Stephenson and others. The textile industries, the steam engine,
railways, and the scores of industries they called into being, all called
for better and stronger means of production. While the rapidity of the
development was due partly to the pressure of this demand, a
second element, that of cumulative experience, was present, and
can be clearly traced. Wilkinson was somewhat of an exception, as
he was primarily an iron master and not a tool builder, so his
relationship to other tool builders is not so direct or clear. But the
connection between Bramah, Maudslay, Clement, Whitworth and
Nasmyth, is shown in the “genealogical” table in Fig. 5.
Bramah had a shop in London where, for many years, he
manufactured locks and built hydraulic machinery and woodworking
tools. Maudslay, probably the finest mechanician of his day, went to
work for Bramah when only eighteen years old and became his
foreman in less than a year. He left after a few years and started in
for himself, later taking Field into partnership, and Maudslay &
Field’s became one of the most famous shops in the world.
Sir Samuel Bentham, who was inspector general of the British
navy, began the design of a set of machines for manufacturing pulley
blocks at the Portsmouth navy yard. He soon met Marc Isambard
Brunel, a brilliant young Royalist officer, who had been driven out of
France during the Revolution, and had started working on block
machinery through a conversation held at Alexander Hamilton’s
dinner table while in America a few years before. Bentham saw the
superiority of Brunel’s plans, substituted them for his own, and
commissioned him to go ahead.
In his search for someone to build the machinery, Brunel was
referred to Maudslay, then just starting in for himself. Maudslay built
the machines, forty-four in all, and they were a brilliant success.
There has been considerable controversy as to whether Bentham or
Brunel designed them. While Maudslay’s skill appears in the
practical details, the general scheme was undoubtedly Brunel’s. In a
few of the machines Bentham’s designs seem to have been used,
but he was able enough and generous enough to set aside most of
his own designs for the better ones of Brunel.
Of the earlier tool builders, Maudslay was the greatest. He, more
than any other, developed the slide-rest and he laid the basis for the
lathe, planer and slotter. His powerful personality is brought out in
Nasmyth’s autobiography written many years later. Nasmyth was a
young boy, eager, with rare mechanical skill and one ambition, to go
to London and work for the great Mr. Maudslay. He tells of their
meeting, of the interest aroused in the older man, and of his being
taken into Maudslay’s personal office to work beside him. It is a
pleasing picture, the young man and the older one, two of the best
mechanics in all England, working side by side, equally proud of
each other.
Joseph Clement came to London and worked for Bramah as chief
draftsman and as superintendent of his works. After Bramah’s death
he went to Maudslay’s and later went into business for himself. He
was an exquisite draftsman, a fertile inventor, and had a very
important part in the development of the screw-cutting lathe and
planer. Joseph Whitworth, the most influential tool builder of the
nineteenth century, worked for Maudslay and for Clement and took
up their work at the point where they left off. Under his influence
machine tools were given a strength and precision which they had
never had before. Richard Roberts was another pupil of Maudslay’s
whose influence, though important, was not so great as that of the
others.
We have an excellent example of what this succession meant.
Nasmyth tells of the beautiful set of taps and dies which Maudslay
made for his own use, and that he standardized the screw-thread
practice of his own shop. Clement carried this further. He established
a definite number of threads per inch for each size, extended the
standardization of threads, and began the regular manufacture of
dies and taps. He fluted the taps by means of milling cutters and
made them with small shanks, so that they might drop through the
tapped hole. Whitworth, taking up Clement’s work, standardized the
screw threads for all England and brought order out of chaos.
Some account of the growth of machine tools in the hands of
these men will be given later. Enough has been said here to show
the cumulative effect of their experience, and its part in the industrial
advance of the first half of the nineteenth century. Similar
successions of American mechanics will be shown later.
Writing from the standpoint of fifty years ago, Smiles quotes Sir
William Fairbairn: “‘The mechanical operations of the present day
could not have been accomplished at any cost thirty years ago; and
what was then considered impossible is now performed with an
exactitude that never fails to accomplish the end in view.’ For this we
are mainly indebted to the almost creative power of modern machine
tools, and the facilities which they present for the production and
reproduction of other machines.”[11]
[11] Smiles: “Industrial Biography,” p. 399.
CHAPTER II
WILKINSON AND BRAMAH
In the previous chapter it was stated that John Wilkinson, of
Bersham, made the steam engine commercially possible by first
boring Watt’s cylinders with the degree of accuracy necessary, and
that his boring machine was probably the first metal-cutting tool
capable of doing large work with anything like modern accuracy.
Although Wilkinson was not primarily a tool builder but an iron
master, this achievement alone is sufficient to make him interesting
to the tool builders of today.
He was born in 1728. His father made his financial start by
manufacturing a crimping iron for ironing the fancy ruffles of the day.
John Wilkinson first started a blast furnace at Belston and later
joined his father in an iron works the latter had built at Bersham, near
Chester. By developing a method of smelting and puddling iron with
coal instead of wood-charcoal, he obtained an immense commercial
advantage over his rivals and soon became a powerful factor in the
iron industry. Later, he built other works, notably one at Broseley,
near Coalbrookdale on the Severn.
One of the important branches of his work was the casting and
finishing of cannon. It was in connection with this that he invented
the boring machine referred to. He bored the first cylinder for Boulton
& Watt in 1775. Farey, in his “History of the Steam Engine,” says:
In the old method, the borer for cutting the metal was not guided in its
progress,[12] and therefore followed the incorrect form given to the cylinder in
casting it; it was scarcely insured that every part of the cylinder should be circular;
and there was no certainty that the cylinder would be straight. This method was
thought sufficient for old engines; but Mr. Watt’s engines required greater
precision.
[12] See Fig. 1.
Mr. Wilkinson’s machine, which is now the common boring-machine, has a
straight central bar of great strength, which occupies the central axis of the
cylinder, during the operation of boring; and the borer, or cutting instrument, is
accurately fitted to slide along this bar, which, being made perfectly straight,
serves as a sort of ruler, to give a rectilinear direction to the borer in its progress,
so as to produce a cylinder equally straight in the length, and circular in the
circumference. This method insures all the accuracy the subject is capable of; for if
the cylinder is cast ever so crooked, the machine will bore it straight and true,
provided there is metal enough to form the required cylinder by cutting away the
superfluities.[13]
[13] Farey: “Treatise on the Steam Engine,” p. 326. 1827.
Wilkinson’s relations with Boulton & Watt became very intimate.

He showed his confidence in the new engine by ordering the first
one built at Soho to blow the bellows of his iron works at Broseley.
Great interest was felt in the success of this engine. Other iron
manufacturers suspended their building operations to see what the
engine could do and Watt himself superintended every detail of its
construction and erection. Before it was finished Boulton wrote to
Watt:
Pray tell Mr. Wilkinson to get a dozen cylinders cast and bored from 12 to 50
inches in diameter, and as many condensers of suitable sizes; the latter must be
sent here, as we will keep them ready fitted up, and then an engine can be turned
out of hand in two or three weeks. I have fixed my mind upon making from 12 to 15
reciprocating, and 50 rotative engines per annum.[14]
[14] Smiles: “Boulton & Watt,” p. 185. London, 1904.
This letter is interesting as showing Boulton’s clear grasp of the

principles of manufacturing. Later, when Boulton & Watt were hard
pressed financially, Wilkinson took a considerable share in their
business and when the rotative engine was developed he ordered
the first one. He consequently has the honor of being the purchaser
of the first reciprocating and the first rotary engine turned out by
Watt. Later, when Watt was educating his son to take up his work, he
sent him for a year to Wilkinson’s iron works at Bersham, to learn
their methods.
Fig. 7, taken from an old encyclopedia of manufacturing and
engineering, shows the boring machine used for boring Watt’s steam
cylinders.
On two oaken stringers SS, frames FF were mounted which
carried a hollow boring bar A driven from the end. The cylinder to be
bored was clamped to saddles, as shown. The cutters were carried
on a head which rotated with the bar and was fed along it by means
of an internal feed-rod and rack. In the machine shown the feeding
was done by a weight and lever which actuated a pinion gearing with
the rack R, but later a positive feed, through a train of gears
operated by the main boring-bar, was used. Two roughing cuts and a
finishing cut were used, and the average feed is given as ¹⁄₁₆ inch
per revolution. While this machine may seem crude, a comparison
with Smeaton’s boring machine, Fig. 1, will show how great an
advance it was over the best which preceded it.
Wilkinson was a pioneer in many lines. He built and launched the
first iron vessel and in a letter dated July 14, 1787, says:
Yesterday week my iron boat was launched. It answers all my expectations, and
has convinced the unbelievers who were 999 in a thousand. It will be only a nine
days wonder, and then be like Columbus’s egg.[15]
[15] “Beiträge zur Geschichte der Technik und Industrie,” 3. Band. S.
227. Berlin, 1911.
In another letter written a little over a year later, he says:

There have been launched two Iron Vessels in my service since Sept. 1st: one is
a canal boat for this [i.e., Birmingham] navigation, the other a barge of 40 tons for
the River Severn. The last was floated on Monday and is, I expect, at Stourport
with a loading of bar iron. My clerk at Broseley advises me that she swims
remarkably light and exceeds my expectations.[16]
[16] Ibid., 3. Band. S. 227.
In 1788 William Symington built and ran a steam-operated boat on

Dalswinton Loch in Scotland, which was a small, light craft with two
hulls, made of tinned sheet-iron plates.[17] It has been erroneously
claimed that this was the first iron boat. It was at best the second.
Although of no commercial importance, it is of very great historical
interest as it antedated Fulton’s “Clermont” by many years.
[17] Autobiography of James Nasmyth, p. 30. London, 1883.
Twenty-three years later, in 1810, Onions & Son of Broseley built
the next iron boats, also for use upon the Severn. Five years later
Mr. Jervons of Liverpool built a small iron boat for use on the Mersey.
In 1821 an iron vessel was built at the Horsley works in
Staffordshire, which sailed from London to Havre and went up the
Seine to Paris.[18] Iron vessels were built from time to time after that,
but it was fully twenty-five years before they came into general use.
[18] Smiles: “Men of Invention and Industry,” pp. 51-52. New York, 1885.
Figure 6. John Wilkinson
Figure 7. Wilkinson’s Boring Machine
Used for Machining the Cylinders of Watt Engines
With Abraham Darby, 3d, Wilkinson has the honor of having built,
in 1779, the first iron bridge, which spanned the Severn at Broseley.
This bridge had a span of 100 feet 6 inches, and a clear height of 48
feet, and is standing today as good as ever.[19] He invented also the
method of making continuous lead pipe.
[19] Smiles: “Industrial Biography,” p. 119. Boston, 1864. Also, Beiträge,
etc., 3. Band. S. 226.
He was a man of great ability, strong and masterful. Boulton wrote

of him to Watt:
I can’t say but that I admire John Wilkinson for his decisive, clear, and distinct
character, which is, I think, a first-rate one of its kind.[20]
[20] Smiles: “Boulton & Watt,” p. 438. London, 1904.
There is a note of qualification in the last clause. With all his

admirable qualities Wilkinson was not always amiable and he was in
constant feud with the other members of his family. He became very
wealthy, but his large estate was dissipated in a famous lawsuit
between his heirs.
Forceful and able as Wilkinson was, another man, Joseph
Bramah, living in London about the same time, had a much more
direct influence on tool building. Bramah was a Yorkshire farmer’s
boy, born in 1748, and lame.[21] As he could not work on the farm he
learned the cabinet maker’s trade, went to London, and, in the
course of his work which took him into the well-to-do houses about
town, he made his first successful invention—the modern water-
closet. He patented it in 1778 and 1783, and it continues to this day
in substantially the same form. In 1784 he patented a lock, which
was an improvement on Barron’s, invented ten years before, and
was one of the most successful ever invented. For many years it had
the reputation of being absolutely unpickable. Confident of this,
Bramah placed a large padlock on a board in his shop window in
Piccadilly and posted beneath it the following notice:
“The artist who can make an instrument that will pick or open this lock shall
receive two hundred guineas the moment it is produced.”
[21] The best account of Bramah is given in Smiles’ “Industrial
Biography,” pp. 228-244. Boston, 1864.
Many tried to open it. In one attempt made in 1817, a clever

mechanic named Russell spent a week on it and gave it up in
despair. In 1851 Alfred C. Hobbs, an American, mastered it and won
the money. He was allowed a month in which to work and the
Committee of Referees in their report stated that he spent sixteen
days, and an actual working time of fifty-one hours, in doing it. This
gave Hobbs a great reputation, which he enhanced by picking every
other lock well known in England at that time, and then showing how
it was done.
This started up the liveliest kind of a controversy and gave
everyone a chance to write to the Times. They all began first picking,
then tearing each other’s locks. Headlines of “Love (Hobbs?) Laughs
at Locksmiths,” “Equivocator” and other like terms appeared.[22]
[22] Price: “Fire and Thief-proof Depositories, and Locks and Keys.”
It was finally recognized that any lock could be picked by a skillful

mechanic with a knowledge of locks, if he were given time enough.
The old Bramah lock, made, by the way, by Henry Maudslay himself,
did not fare so badly. Hobbs had unmolested access to it for days
with any tools he could bring or devise; and though he finally opened
it, a lock probably sixty years old which could stand such an assault
for fifty hours was secure for all ordinary purposes.[23]
[23] Anyone who is interested can find an account of the affair in Price’s
“Fire and Thief-proof Depositories, and Locks and Keys,” published in 1856,
and Mr. Hobbs has given his own personal account of it, explaining how the
work was done, in the Trans. of the A. S. M. E., Vol. VI, pp. 248-253.
When Bramah began manufacturing the locks he found almost

immediately that they called for a better quality of workmanship than
was available, with even the best manual skill about him. A series of
machine tools had to be devised if they were to be made in the
quantities and of the quality desired. He turned first to an old
German in Moodie’s shop who had the reputation of being the most
ingenious workman in London; but while he, with Bramah, saw the
need, he could not meet it. One of his shopmates, however,
suggested a young man at the Woolwich Arsenal named Henry
Maudslay, then only eighteen years old.
Bramah sent for him and Maudslay soon became his right-hand
man, and was made superintendent of the works at nineteen. The
work of these two men in developing the tools needed laid the
foundation for the standard metal-cutting tools of today. The most
important improvement was the slide-rest. Nasmyth later said that he
had seen the first one, made by Maudslay, running in Bramah’s shop
and that “in it were all those arrangements which are to be found in
the most modern slide-rest of our own day” (i.e., fifty years later).
Other parts of the metal-cutting lathe also began to take shape; it
has been said that parts of the lock were milled on a lathe with rotary
cutters, and that the beginnings of the planer were made. How much
of this work was Bramah’s and how much Maudslay’s it would be
hard to say. Bramah was a fertile, clever inventor; but Maudslay was
the better general mechanic, had a surer judgment and a greater
influence on subsequent tool design.
About this time Bramah invented the hydraulic press. As he first
built it, the ram was packed with a stuffing-box and gland. This
gripped the ram, retarded the return stroke, and gave him a lot of
trouble until Maudslay substituted the self-tightening cup-leather
packing for the stuffing-box, an improvement which made the device
a success.
Bramah’s restless ingenuity was continually at work. He invented a
very successful beer-pump in 1797, the four-way cock, a quill
sharpener which was in general use until quills were superseded by
steel pens, and he dabbled with the steam engine. He was a bitter
opponent of Watt and testified against him in the famous suit of
Boulton & Watt against Hornblower. He maintained the superiority of
the old Newcomen engines and said that the principle of the
separate condenser was fallacious, that Watt had added nothing
new which was not worthless, and that his so-called improvements
were “monstrous stupidity.”
In 1802 Bramah obtained a patent for woodworking machinery
second only in importance to that granted Bentham in 1791. Like
Bentham, he aimed to replace manual labor “for producing straight,
smooth, and parallel surfaces on wood and other materials requiring
truth, in a manner much more expeditious and perfect than can be
performed by the use of axes, saws, planes, and other cutting
instruments used by hand in the ordinary way.” His tools were
carried in fixed frames and driven by machinery. In his planing
machine, one of which was running in the Woolwich Arsenal for fifty
years, the cutter-head, which carried twenty-eight tools, was
mounted on a vertical shaft and swept across the work in a
horizontal plane. He used this same method in planing the metal
parts for his locks, which corresponds, of course, to our modern
face-milling. He provided for cutting spherical and concave surfaces
and used his device for making wooden bowls.
In 1806 he devised an automatic machine which the Bank of
England used many years in numbering their banknotes, eliminating
error and saving the labor of many clerks.
Maudslay was in his employ from 1789 to 1797. He was getting as
superintendent 30s. ($7.50) a week. A growing family and “the high
cost of living” rendered this insufficient and he applied for more. He
was refused so curtly that he gave up his position and started in for
himself in a small workshop on Oxford Street in London. Later he
took Field in as partner under the firm name of Maudslay & Field.
In 1813 Bramah engaged another man who later had a great
influence, Joseph Clement. Clement soon became his chief
draftsman and superintendent. Salaries had gone up somewhat by

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About the Author ii

3.7 Dendritic Cells 55

7.1 Introduction 110

8.1 Introduction 133

9.1 Introduction 159

10.1 Introduction 178

11.1 Introduction 199

12.1 Introduction 218

13.1 Introduction 245

14.1 Introduction 270

15.1 Introduction 294

16.1 Introduction 310

16.5 The Paradox: Tumors Elude the Immune System 318

Types of Grafts 325

Radioimmunoassay (RIA) 330

● Important terminologies highlighted

●Chapter end questions: 326

Edward Jenner’s pioneering contributions enabled the eradication

1. Innate and Adaptive Immunity

immunity is characterized by specificity, recognition of self/nonself molecules and a unique property

Cell mediated immune response and Humoral immune response

What is Sickle Cell Anemia?

MECHANISMS OF INNATE IMMUNITY

Bacterial cell wall

Complement fragment/CRP ENHANCED

3. Other chemical barriers

++ = About 100%; + = About 25%; +/– = Rare < 5%

5. Endocytic and phagocytic barriers

Extracellular fluid Extracellular fluid

Vesicle Coated pit

This kind of immunity is also developed

What is Serum sickness?

entry of pathogens in to our body through Virus

Type of response Antigen independent, Cell mediated Antigen dependent, Humoral

SHORT ANSWER QUESTIONS

ESSAY TYPE QUESTIONS

The second question as to who brought this change about is not

Take the slide-rest. It is clearly shown in the French encyclopedia

Blanchard was by no means the first to turn irregular forms on a

Figure 5. Genealogy of the Early English Tool Builders

To the third question as to why this development when once begun

Wilkinson’s relations with Boulton & Watt became very intimate.

This letter is interesting as showing Boulton’s clear grasp of the

In another letter written a little over a year later, he says:

In 1788 William Symington built and ran a steam-operated boat on

Used for Machining the Cylinders of Watt Engines

He was a man of great ability, strong and masterful. Boulton wrote

There is a note of qualification in the last clause. With all his

Many tried to open it. In one attempt made in 1817, a clever

It was finally recognized that any lock could be picked by a skillful