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 Translational Immunology
TRANSLATIONAL AUTOIMMUNITY,
VOL. 3
This page intentionally left blank
 Translational Immunology
TRANSLATIONAL
AUTOIMMUNITY,
VOL. 3
Autoimmune Disease Associated
with Different Clinical Features

Edited by

Nima Rezaei
Professor, Department of Immunology, School of Medicine;
Head, Research Center for Immunodeficiencies, Children’s Medical Center,
Tehran University of Medical Sciences; Founding President,
Universal Scientific Education and Research Network (USERN),
Tehran, Iran

Editorial Assistant

Niloufar Yazdanpanah
Managing Director, Network of Immunity in Infection,
Malignancy and Autoimmunity (NIIMA),
Universal Scientific Education and Research Network, (USERN); and School of Medicine,
Tehran University of Medical Sciences,
Tehran, Iran
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 Dedication

This book would not have been possible without the continuous encouragement from my family.
I dedicate this book to my daughters, Ariana and Arnika, with the hope that we learn
enough from today to make a brighter future for the next generation.
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 Contents

Contributors xi 3. Autoimmunity regulation within the

Preface xv tumor microenvironment
Series editor biography xvii Irina Palacín-Aliana, Josefa Carrión-Navarro,
Ángel Ayuso-Sacido, and Noemí García-Romero
Acknowledgment xix
Abbreviations xxi 1 Introduction 52
2 Targeting immune checkpoints in cancer
immunotherapy 53
3 Coinhibitory checkpoint pathways
1. Introduction on autoimmunity to cancer 54
and associated conditions 4 Costimulatory checkpoint pathways on
Nima Rezaei and Niloufar Yazdanpanah cancer 60
5 Conclusion 63
1 Introduction 1 References 63
2 Autoimmunity and infection 2
3 Autoimmunity and genetic syndromes 3
4 Autoimmunity and inborn errors of 4. Mechanisms of immune tolerance
immunity 6 breakdown in inborn errors of immunity
5 Autoimmunity and malignancies 8 Giuliana Giardino, Emilia Cirillo, Rosaria Prencipe, Roberta
6 Autoimmunity and associated conditions affecting Romano, Francesca Cillo, Elisabetta Toriello, Veronica De Rosa, and
Claudio Pignata
patients’ quality of life 8
7 Conclusion 9
1 Introduction 74
References 9
2 Mechanisms implicated in the disruption of
immune tolerance in IEI 74
2. Cross talks between 3 Central tolerance disruption 75
autoimmunity and cancer 4 Alterations of peripheral tolerance 83
Thalita Basso Scandolara, Leticia Madureira Pacholak, Isabella 5 Conclusion 88
Morais Tavares, Rodrigo Kern, Leonardo Garcia-Velazquez, and References 89
Carolina Panis

1 Introduction 16 5. Autoimmunity in combined

2 Autoimmunity and cancer mechanisms: Clinical immunodeficiency
features and similar mechanisms 18 Andrew R. Gennery
3 Rheumatoid arthritis 28
4 Systemic lupus erythematosus 29 1 Introduction 97
5 Sjögren’s syndrome 29 2 Severe combined immunodeficiencies 101
6 Systemic sclerosis 29 3 Combined immunodeficiencies 106
7 Idiopathic inflammatory myopathy 30 4 Combined immunodeficiencies associated with
8 ANCA-associated vasculitis 30 significant autoimmunity 106
9 Conclusion 39 5 Combined immunodeficiencies rarely associated
References 40 with autoimmunity 112

vii
viii Contents

6 Combined immunodeficiencies not associated 9. Autoimmunity and infertility

with autoimmunity 115 Tao Zhang, Xiaoyan Chen, Tin Chiu Li, Chi Chiu Wang,
7 Conclusion 120 and Jacqueline Pui Wah Chung
References 120
1 Introduction 186
6. Autoimmunity and autoimmune diseases 2 The association between autoimmunity and
female infertility 186
in primary selective IgM deficiency
3 The association between autoimmunity and male
Sudhir Gupta and Ankmalika Gupta
infertility 193
4 Clinical implications of serum autoantibodies in
1 Introduction 129
IVF/ICSI-ET 195
2 Natural IgM antibodies 130
5 Conclusion 200
3 Role of IgM in autoimmunity and autoimmune
References 200
diseases 131
4 Autoimmunity and autoimmune diseases
in selective IgM deficiency 134 10. Autoimmune disease of the
5 Conclusion 136 cardiovascular system
References 136 Davood Shafie

7. Autoimmunity and HIV infection 1 Introduction 207

2 Rheumatic heart disease 208
Luis Ramos Ruperto, Carmen Busca Arenzana,
Angel Robles Marhuenda, and Jose I. Bernardino
3 Myocarditis 209
4 Vasculitis 213
1 Introduction 141 5 Conclusion 221
2 HIV structure 142 References 221
3 HIV infection 142
4 HIV and autoimmunity 149 11. Allergy and autoimmunity:
5 Autoimmune diseases in the HIV patient 156 Share of genetics and environment
6 Conclusion 161 Kalaivani Manibarathi, Chit Tong Lio, and Tanima Bose
References 161
1 Introduction 232
8. Autoimmune diseases and metabolic 2 Key elements regulating allergy and autoimmune
disorders: Molecular connections disease 232
3 Immunopathological reactions—Allergy and
and potential therapeutic targets autoimmunity subtypes 247
Md Jamal Uddin, Dang Khoa Tran, Md Abdul Hannan, 4 Conclusion 250
Hasan-Al-Faruque, Md. Ataur Rahman, Akhi Moni, Nguyen Thanh
Lam, Vo Truong Nhu Ngoc, and Dinh-Toi Chu
References 251

1 Introduction 170 12. Asthma and autoimmunity

2 Molecular mechanisms of autoimmune responses Ourania S. Kotsiou
and autoimmune diseases 171
3 Molecular connections between autoimmune 1 Introduction 261
diseases and some important metabolic 2 Asthma endotypes—An overview 262
disorders 173 3 Autoimmune responses following chronic
4 Potential molecular targets to control autoimmune inflammation 265
diseases and metabolic disorders 178 4 Asthma and autoimmunity 265
5 Conclusion 179 5 Conclusion 278
References 180 References 279
 ix
Contents  

13. Autoimmunity in interstitial 9 Cell-mediated autoimmune lung damage in the

lung disease pathogenesis of stable COPD and pulmonary
emphysema 323
Gianluca Sambataro, Domenico Sambataro,
Veronica Adiletta, and Paolo Maria Leone 10 Therapeutic implications 324
11 Conclusion 325
1 Introduction 291 References 325
2 Interstitial lung disease in systemic
sclerosis 293 15. Oxidative stress in oral autoimmune
3 Rheumatoid arthritis 298 disorders
4 Other rheumatic conditions associated Mahdieh-Sadat Moosavi
with ILD 303
5 Conclusion 304 1 Introduction 333
References 304 2 Oxidative stress and the immune system 334
3 Biomarkers of oxidative stress in oral autoimmune
disorders 335
14. Role of autoimmunity in the 4 Antioxidants and related treatments for oral
pathogenesis of chronic obstructive autoimmune disorders 338
pulmonary disease and pulmonary 5 Conclusion 340
emphysema References 341
Francesco Nucera, Phil M. Hansbro, Vincenzo Casolaro,
Ramapraba Appanna, Paul Kirkham, Ian M. Adcock, and 16. Autoimmunity and psychosis
Gaetano Caramori
Milica M. Borovcanin, Marija Milovanovic, Katarina Vesic,
Nemanja N. Muric, Jelena Milovanovic,
1 Introduction 312 Aleksandar N. Arsenijevic, and Nebojsa N. Arsenijevic
2 Animal models of chronic obstructive
pulmonary disease (COPD) and pulmonary 1 Introduction 343
emphysema 312 2 Infection, inflammation, and autoimmunity in
3 Autoimmune responses in the pathogenesis psychosis 344
of stable COPD and pulmonary emphysema 315 3 Mechanisms of autoimmunity in the central
4 Regulatory T (Treg) cells in the autoimmune nervous system 346
pathogenesis of stable COPD and pulmonary 4 Autoimmune encephalitis and psychosis 348
emphysema 318 5 Multiple sclerosis and psychosis 350
5 B-cells and autoantibody-mediated lung damage in 6 Autoimmune epilepsy and psychosis 352
the pathogenesis of stable COPD and pulmonary 7 Nonneurological autoimmune disorders and
emphysema 318 psychosis 353
6 Other autoantibodies in COPD and pulmonary 8 Possible causal treatment of psychosis in
emphysema 321 autoimmune diseases 356
7 Complement system and autoimmunity in COPD 9 Conclusion 356
and pulmonary emphysema 322 References 357
8 Role of the microbiota in COPD and pulmonary
emphysema 323 Index 367
This page intentionally left blank
 Contributors
Ian M. Adcock National Heart and Lung Insti-
tute, Imperial College London, London, United
Kingdom
Veronica Adiletta Fondazione Policlinico A.
Gemelli IRCCS, Università Cattolica del Sacro
Cuore, Rome, Italy
Ramapraba Appanna Department of Medicine,
Surgery and Dentistry “Scuola Medica Salerni-
tana”, University of Salerno, Salerno, Italy
Carmen Busca Arenzana HIV Unit, Department
of Internal Medicine, Hospital Universitario La
Paz, IdiPAZ, Madrid, Spain
Aleksandar N. Arsenijevic Center for Molecu-
lar Medicine and Stem Cell Research, Faculty
of Medical Sciences, University of Kragujevac,
Kragujevac, Serbia
Nebojsa N. Arsenijevic Center for Molecular
Medicine and Stem Cell Research, Faculty of
Medical Sciences, University of Kragujevac,
Kragujevac, Serbia
Ángel Ayuso-Sacido Faculty of Experimental
Sciences, Universidad Francisco de Vitoria;
Brain Tumor Laboratory, Fundación Vithas,
Grupo Hospitales Vithas; Faculty of Medicine,
Universidad Francisco de Vitoria, Madrid,
Spain
Jose I. Bernardino HIV Unit, Department of
Internal Medicine, Hospital Universitario La
Paz, IdiPAZ, Madrid, Spain
Milica M. Borovcanin Department of Psychia-
try, Faculty of Medical Sciences, University of
Kragujevac, Kragujevac, Serbia
Tanima Bose Institute for Clinical Neuroim-
munology, Ludwig Maximilian University of
Munich (LMU), Munich, Germany
Gaetano Caramori Pulmonology, Depart-
ment of Biomedical Sciences, Dentistry and
Morphological
­ and Functional Imaging
xi
(BIOMORF), University of Messina, Messina,
Italy
Josefa Carrión-Navarro Faculty of Experimen-
tal Sciences, Universidad Francisco de Vitoria,
Madrid, Spain
Vincenzo Casolaro Department of Medicine,
Surgery and Dentistry “Scuola Medica Salerni-
tana”, University of Salerno, Salerno, Italy
Xiaoyan Chen Department of Obstetrics and
Gynaecology, Faculty of Medicine, The Chinese
University of Hong Kong, Prince of Wales
Hospital, Shatin, Hong Kong Special Admin-
istrative Region; Shenzhen Baoan Women’s
and Children’s Hospital, Shenzhen University,
Shenzhen, China
Dinh-Toi Chu Center for Biomedicine and
Community Health, VNU-International School,
Hanoi, Viet Nam
Jacqueline Pui Wah Chung Department of
Obstetrics and Gynaecology, Faculty of Med-
icine, The Chinese University of Hong Kong,
Prince of Wales Hospital, Shatin, Hong Kong
Special Administrative Region
Francesca Cillo Department of Translational
Medical Sciences—Section of Pediatrics, Uni-
versity of Naples Federico II, Naples, Italy
Emilia Cirillo Department of Translational
Medical Sciences—Section of Pediatrics, Uni-
versity of Naples Federico II, Naples, Italy
Noemí García-Romero Faculty of Experimen-
tal Sciences, Universidad Francisco de Vitoria,
Madrid, Spain
Leonardo Garcia-Velazquez University of
Paraná, Unipar, Paraná, Brazil
Andrew R. Gennery Translational and Clinical
Research Institute, Newcastle University, Paediat-
ric Immunology + HSCT, Great North ­Children’s
Hospital, Newcastle upon Tyne, United Kingdom
xii Contributors
Giuliana Giardino Department of Translational
Medical Sciences—Section of Pediatrics, Uni-
versity of Naples Federico II, Naples, Italy
Ankmalika Gupta Foundation for Primary
Immunodeficiency Diseases, Newport Beach,
CA, United States
Sudhir Gupta Division of Basic and Clinical
Immunology, University of California at Irvine,
Irvine, CA, United States
Md Abdul Hannan Department of Bio-
chemistry and Molecular Biology, Bangla-
desh Agricultural University, Mymensingh,
Bangladesh
Phil M. Hansbro Centre for Inflammation,
Centenary Institute and University of Technol-
ogy Sydney, Faculty of Science, Sydney, NSW,
Australia
Hasan-Al-Faruque ABEx Bio-Research Center,
Dhaka, Bangladesh; Division of Biotechnology,
Daegu Gyeongbuk Institute of Science and
Technology, Daegu, Republic of Korea
Rodrigo Kern Laboratory of Tumor Biology,
Post-Graduation Program in Applied Health
Sciences, State University of West Paraná,
Unioeste, Paraná, Francisco Beltrão, Brazil
Paul Kirkham Department of Biomedical Sci-
ences and Physiology, School of Medicine, Uni-
versity of Wolverhampton, Wolverhampton,
United Kingdom
Ourania S. Kotsiou Faculty of Nursing, School
of Health Sciences, University of Thessaly,
Larissa, Greece
Nguyen Thanh Lam Center for Biomedicine
and Community Health, VNU-International
School, Hanoi, Viet Nam
Paolo Maria Leone Fondazione Policlinico A.
Gemelli IRCCS, Università Cattolica del Sacro
Cuore, Rome, Italy
Tin Chiu Li Department of Obstetrics and
Gynaecology, Faculty of Medicine, The
Chinese University of Hong Kong, Prince of
Wales Hospital; Chinese University of Hong
Kong-Sichuan University Joint Laboratory in
Reproductive Medicine, The Chinese Univer-
sity of Hong Kong, Shatin, Hong Kong Special
Administrative Region
Chit Tong Lio Chair of Experimental Bioin-
formatics, Technical University of Munich,
Freising; Chair of Computational Systems
­
Biology, University of Hamburg, Hamburg,
Germany
Kalaivani Manibarathi Department of Neu-
rodegenerative Diseases, Hertie-Institute for
Clinical Brain Research and Center of Neurol-
ogy, University of Tübingen; Center for Neu-
rodegenerative Diseases (DZNE), Tübingen,
Germany
Angel Robles Marhuenda Autoimmune Dis-
eases Unit, Department of Internal Medicine,
Hospital Universitario La Paz, Madrid, Spain
Jelena Milovanovic Center for Molecular
Medicine and Stem Cell Research, Faculty of
Medical Sciences, University of Kragujevac,
Kragujevac, Serbia
Marija Milovanovic Center for Molecular
Medicine and Stem Cell Research, Faculty of
Medical Sciences, University of Kragujevac,
Kragujevac, Serbia
Akhi Moni ABEx Bio-Research Center, Dhaka,
Bangladesh
Mahdieh-Sadat Moosavi Oral and Maxillofa-
cial Medicine Department, School of Dentistry,
Tehran University of Medical Sciences, Tehran,
Iran
Nemanja N. Muric Department of Psychiatry,
Faculty of Medical Sciences, University of
Kragujevac, Kragujevac, Serbia
Vo Truong Nhu Ngoc School of Odonto
Stomatology, Hanoi Medical University, Hanoi,
Viet Nam
Francesco Nucera Pulmonology, Department of
Biomedical Sciences, Dentistry and Morpho-
logical and Functional Imaging (BIOMORF),
University of Messina, Messina, Italy
Leticia Madureira Pacholak Laboratory of
Tumor Biology, Post-Graduation Program in
Applied Health Sciences, State University
of West Paraná, Unioeste, Paraná, Francisco
Beltrão, Brazil
Irina Palacín-Aliana Atrys Health, Barcelona;
Fundación de Investigación HM Hospitales,
HM Hospitales, Madrid, Spain
 Contributors
Carolina Panis Laboratory of Tumor Biology,
Post-Graduation Program in Applied Health
Sciences, State University of West Paraná,
Unioeste, Paraná, Francisco Beltrão, Brazil
Claudio Pignata Department of Translational
Medical Sciences—Section of Pediatrics, Uni-
versity of Naples Federico II, Naples, Italy
Rosaria Prencipe Institute of Experimen-
tal Endocrinology and Oncology, National
Research Council, Naples, Italy
Md. Ataur Rahman ABEx Bio-Research Center,
Dhaka, Bangladesh; Center for Neuroscience,
Korea Institute of Science and Technology
(KIST), Seoul, Republic of Korea
Nima Rezaei Research Center for Immu-
nodeficiencies, Children's Medical Center;
Department of Immunology, School of Med-
icine, Tehran University of Medical Sciences;
Network of Immunity in Infection, Malig-
nancy and Autoimmunity (NIIMA), Universal
Scientific Education and Research Network
(USERN), Tehran, Iran
Roberta Romano Department of Translational
Medical Sciences—Section of Pediatrics, Uni-
versity of Naples Federico II, Naples, Italy
Veronica De Rosa Institute of Experimen-
tal Endocrinology and Oncology, National
Research Council, Naples, Italy
Luis Ramos Ruperto Autoimmune Diseases
Unit, Department of Internal Medicine, Hospi-
tal Universitario La Paz, Madrid, Spain
Domenico Sambataro Artroreuma s.r.l., Outpa-
tient Clinic of Rheumatology Associated With the
National Health System, Mascalucia (CT), Italy
Gianluca Sambataro Department of Clinical
and Experimental Medicine, Regional Referral
Center for Rare Lung Diseases, “Policlinico S.
Marco”, University of Catania, Catania; Artro-
reuma s.r.l., Outpatient Clinic of Rheumatology
Associated With the National Health System,
Mascalucia (CT), Italy
Thalita Basso Scandolara Post-Graduation
Program in Biological Sciences (Genetics),
Federal University of Rio de Janeiro, UFRJ,
xiii
Rio de Janeiro; Laboratory of Tumor Biology,
Post-Graduation Program in Applied Health
Sciences, State University of West Paraná,
Unioeste, Paraná, Francisco Beltrão, Brazil
Davood Shafie Heart Failure Research Center,
Cardiovascular Research Institute, Isfahan Uni-
versity of Medical Sciences, Isfahan, Iran
Isabella Morais Tavares University of Paraná,
Unipar, Paraná, Brazil
Elisabetta Toriello Department of Translational
Medical Sciences—Section of Pediatrics, Uni-
versity of Naples Federico II, Naples, Italy
Dang Khoa Tran Department of Anatomy,
Pham Ngoc Thach University of Medicine, Ho
Chi Minh City, Viet Nam
Md Jamal Uddin Graduate School of Pharma-
ceutical Sciences, College of Pharmacy, Ewha
Womans University, Seoul, Republic of Korea;
ABEx Bio-Research Center, Dhaka, Bangladesh
Katarina Vesic Department of Neurology,
Faculty of Medical Sciences, University of
Kragujevac, Kragujevac, Serbia
Chi Chiu Wang Department of Obstetrics and
Gynaecology, Faculty of Medicine, The Chinese
University of Hong Kong, Prince of Wales Hos-
pital; Li Ka Shing Institute of Health Sciences
and School of Biomedical Sciences, The Chinese
University of Hong Kong; Chinese University
of Hong Kong-Sichuan University Joint Labo-
ratory in Reproductive Medicine, The Chinese
University of Hong Kong, Shatin, Hong Kong
Special Administrative Region
Niloufar Yazdanpanah Research Center for
Immunodeficiencies, Children's Medical
Center; School of Medicine, Tehran University
of Medical Sciences; Network of Immunity
in Infection, Malignancy and Autoimmunity
(NIIMA), Universal Scientific Education and
Research Network (USERN), Tehran, Iran
Tao Zhang Department of Obstetrics and
Gynaecology, Faculty of Medicine, The Chinese
University of Hong Kong, Prince of Wales Hos-
pital, Shatin, Hong Kong Special Administra-
tive Region
This page intentionally left blank
 Preface
The scientific world has witnessed re-
markable developments in the field of im-
munology during recent decades. Novel
discovery of genes related to different
immune-mediated diseases has enhanced
­ Features attempts to highlight the most im-
our knowledge about the immune system
and its interactions with other systems in
the human body and enlightened different
aspects of its complexity that lead to promot-
ing diagnostic strategies, designing more
efficient therapeutic agents, and reducing
potential morbidities and mortality. Due to
the broad spectrum of immune-­mediated
diseases, from immunodeficiency to hy-
persensitivity and autoimmune diseases,
the immune system diseases collectively
contribute to a considerable prevalence, al-
though every single immune-mediated dis-
ease represents a low prevalence.
The responsibility of applying the latest
research findings had long been a concern
for scientists. Translational research is recog-
nized as a potential tool to utilize scientific
findings in clinical settings and patients’ care.
xv
Considering the wide spectrum of diseases re-
lated to the immune system besides the huge
burden for individuals, health care settings,
families, and society, identifying promising al-
ternative diagnostic and therapeutic strategies
through translational studies is of interest.
The Translational Immunology book series
is a major new suite of books in immunol-
ogy, which cover both basic and clinical im-
munology. The series seeks to discuss and
provide foundational content from bench to
bedside in immunology. This series intends
to discuss recent immunological findings
and translate them into clinical practice. The
first volumes of this book series are specifi-
cally devoted to autoimmune diseases.
Translational Autoimmunity: Autoimmune
Disease Associated With Different Clinical
portant comorbidities and medical condi-
tions associated with autoimmune diseases.
Infections are one of the pivotal factors in
inducing autoimmunity. However, patients
with autoimmune diseases are prone to
specific types of infections. Therefore, there
is a bidirectional association between au-
toimmunity and infections. Autoimmune
manifestations have been reported as rep-
resentative symptoms of different genetic
syndromes. Moreover, despite being recog-
nized as different classes in the spectrum of
immune-­ related diseases, ­ autoimmunity is
frequently reported in different types of in-
born errors of immunity (IEIs). Cancer and
autoimmunity each imparts a huge burden
on patients; however, these conditions are
mutually connected, which could multiply
the burden. Autoimmunity could represent
xvi Preface
as a ­manifestation of different cancers, while
the risk of both solid tumors and hematologi-
cal malignancies is enhanced in autoimmune
diseases, mainly due to the chronic inflam-
matory state and different genetic mutations.
Considering the chronic nature of autoim-
mune diseases, it massively affects patients’
quality of life because it is associated with
more morbidities such as infertility, obesity,
and mental disorders. This book starts by re-
capitulating the most important conditions
associated with autoimmune diseases in
Chapter 1, which briefly discusses the possi-
ble shared background of autoimmunity with
each of the associated conditions. Chapters 2
and 3 reveal the complex association between
autoimmunity and cancer. Chapters 4–6 dive
deep into the association of autoimmunity
with IEIs. The importance of human im-
munodeficiency virus (HIV) infection in
the current epidemic of HIV is well known.
Therefore, Chapter 7 is devoted to HIV (ac-
quired immunodeficiency disease (AIDS))
and autoimmunity. Since autoimmune dis-
eases massively affect patients’ quality of
life due to the chronic course of the disease
and the life-long need to take medications,
assessing all the possible medical complica-
tions that could be prevented is of interest. To
achieve this important aim, Chapters 8 and 9
discuss the association of autoimmunity with
metabolic disorders and infertility, respec-
tively. Autoimmunity in respiratory diseases
and autoimmune diseases of the cardiovas-
cular system, as the two vital systems in the
body, is explored in Chapters 10 (cardiovas-
cular diseases), 11 (allergy), 12 (asthma), 13
(interstitial lung disease), and 14 (chronic
obstructive pulmonary disease and emphy-
sema). Chapter 15 portrays one of the im-
portant mechanisms of autoimmune-based
injuries in oral diseases. Finally, Chapter 16
focuses on the association of autoimmune
conditions with mental disorders to further
highlight the role of the immune system in
psychiatric diseases.
The Translational Immunology book series
is the outcome of the invaluable contribution
of scientists and clinicians from well-known
universities/institutes worldwide. I hereby
appreciate and acknowledge the expertise
of all contributors for generously devoting
their time and considerable effort in prepar-
ing their respective chapters. I also express
my gratitude to Elsevier for providing me
the opportunity to publish this book. Finally,
I hope this translational book will be com-
prehensible, cogent, and of special value to
researchers and clinicians who wish to ex-
tend their knowledge on immunology.
Nima Rezaei
 Series editor biography
Professor Nima Rezaei earned his MD from
Tehran University of Medical Sciences and
subsequently obtained an MSc in Molecular
and Genetic Medicine and a PhD in Clinical
Immunology and Human Genetics from the
University of Sheffield, United Kingdom.
He also received a short-term ­fellowship in
xvii
Pediatric Clinical Immunology and Bone
Marrow Transplantation in the Newcastle
General Hospital. Professor Rezaei is now
Full Professor of Immunology and Vice Dean
of International Affairs, School of Medicine,
Tehran University of Medical Sciences, and
the cofounder and head of the Research
Center for Immunodeficiencies. He is also
the founding president of Universal Scientific
Education and Research Network (USERN).
Professor Rezaei has already been the direc-
tor of more than 50 research projects and has
designed and participated in several interna-
tional collaborative projects. Professor Rezaei
is an editorial assistant and board member
for more than 30 international journals. He
has edited more than 30 international books,
presented more than 500 ­lectures/posters in
congresses/­ meetings, and published more
than 1000 scientific papers in international
journals.
This page intentionally left blank
 Acknowledgment

I express my gratitude to the editorial assistant of this book, Dr. Niloufar Yazdanpanah,
without whose contribution this book definitely would not have been completed.

Nima Rezaei

xix
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 Abbreviations

a-ANCA atypical antineutrophil cytoplasmic anti-CCP anti-cyclic citrullinated peptide

antibody antibodies
AAV ANCA-associated vasculitis anti-dsDNA anti-double-stranded DNA
Abs antibodies anti-ENAs antiextractable nuclear antigens
ACA anti-centromere antibodies antibodies
ACA anticardiolipin antibodies AOPP advanced oxidation protein
ACEIs angiotensin-converting enzyme products
inhibitors AP autoimmune psychosis
ACR American College of AP-1 activator protein 1
Rheumatology APCs antigen-presenting cells
AD atopic dermatitis APDS activated phosphoinositide-3-
ADAR1 adenosine deaminase RNA specific kinase δ syndrome
ADCC antibody-dependent cell-mediated APECED autoimmune polyendocrinopathy,
cytotoxicity candidiasis, ectodermal dysplasia
ADCC antibody-dependent cellular aPL antiphospholipid antibodies
cytotoxicity APS anti-phospholipid syndrome
AdMVs apoptosis-derived membrane AR allergic rhinitis
vesicles ARB angiotensin receptor blockers
ADs autoimmune disease ASA anti-sperm antibody
AEC alveolar epithelial cells ASCA anti-Saccharomyces cerevisiae
AERD aspirin-exacerbated respiratory antibodies
disease ATA anti-thyroid antibodies
AGS Aicardi-Goutières syndrome AZA azathiprine
AHR airway hyperresponsiveness B19v parvovirus B19
AI aortic insufficiency BAFF B-cell-activating factor belonging to
AIDS acquired immunodeficiency the TNF family
syndrome BAFF(-R) B-cell-activating factor (receptor)
AIH autoimmune hepatitis BALF bronchoalveolar lavage fluid
AIHA autoimmune hemolytic anemia BALT bronchus-associated lymphoid tissue
AIM apoptosis inhibitor of macrophage BBB blood-brain barrier
AIP-1 autoimmune pancreatitis type-1 BC Behçet’s disease
AIP-2 antiinflammatory protein-2 BCL10 B-cell CLL/lymphoma 10
AIRE autoimmune regulator BCR B-cell receptors
AITD autoimmune thyroid disease bDMARDS biologic disease-modifying anti-
AITP autoimmune thrombocytopenic rheumatic drugs
purpura Blimp-1 B-lymphocyte-induced maturation
ALPS autoimmune lymphoproliferative protein-1
syndrome BLyS B-lymphocyte stimulator
AMPA α-amino-3-hydroxy-5-methyl-4- BMI body mass index
isoxazolepropionic acid BP bullous pemphigoid
ANAs antinuclear antibodies Bregs B regulatory cells
ANCA antineutrophil cytoplasmic BTK Bruton tyrosine kinase
antibodies BTLA B- and T-lymphocyte associated

xxi
xxii Abbreviations

C1, C2, C3, C4, C3a, complement proteins 3a, 3b, 5a, DC dendritic cells
C3b, C5a, C5b-C9 5b-9 DCM dilated cardiomyopathy
C-ANCA cytoplasmic antineutrophil DEDs death-effector domains
cytoplasmic antibody Derp-1 dermatophagoidespteronissinus
CARD11 caspase activation and with protease activity
recruitment domain 11 DHEA dehydroepiandrosterone
cART combination antiretroviral therapy DILS diffuse lymphocyte infiltration
CAT catalase syndrome
CCL chemokine ligand DIP desquamative interstitial
CCL-11 C-C motif chemokine 11 pneumonia
CCP cyclic citrullinated peptide DISC death-inducing signaling complex
CCR7 C-C chemokine receptor type 7 DLBCL diffuse large B-cell lymphoma
CD cluster of differentiation DLCO diffusing lung capacity for carbon
CD25 interleukin-2 receptor α chain monoxide
CD40L CD40 ligand DM dermatomyositis
cDCs/myDCs conventional dendritic cells/ DMARDs disease-modifying anti-rheumatic
myeloid dendritic cells drugs
cDMARDs biologic disease-modifying anti- DNA and RNA deoxyribonucleic acid, Ribonucleic
rheumatic drugs acid
CENP-B centromeric protein B DOCK2 dedicator of cytokinesis 2
CGD chronic granulomatous disease DOCK8 dedicator of cytokinesis 8
CID combined immunodeficiency dsDNA double-stranded DNA
CIPD chronic inflammatory Dsg desmoglein
demyelinating dSSc cutaneous diffuse SSc
polyradiculoneuropathy DTC differentiated thyroid carcinomas
CK cytokeratin DTH/DHR delayed-type hypersensitivity
CLL chronic lymphocytic leukemia EAE experimental autoimmune
CMC chronic mucocutaneous encephalomyelitis
candidiasis EBNA-1 EBV nuclear antigen 1
CMR cardiac magnetic resonance EBV Epstein-Barr virus
CMV cytomegalovirus EC endothelial cells
CNS central nervous system ECM extracellular matrix
COPD chronic obstructive pulmonary ECP eosinophil cationic protein
disease EDN eosinophil-derived neurotoxin
CpG CpGoligodeoxynucleotides EETS eosinophil extracellular traps
CS cigarette smoke EF elastin fragments
CSCC cutaneous squamous cell EGFR epidermal group factor receptor
carcinoma EGPA Churg-Strauss syndrome or
CSF cerebrospinal fluid eosinophilic granulomatosis with
CT computed tomography polyangiitis
CTD connective tissue disease EMA European Medicines Agency
CTLA-4 cytotoxic T-lymphocyte antigen 4 EMB endomyocardial biopsy
CTLs cytotoxic T-lymphocytes EPX eosinophil peroxidase
CTS cathepsin ERK extracellular signal-regulated
CVDs cardiovascular diseases kinase
CVID common variable ERM ezrin-radixin-moesin
immunodeficiency EULAR European League against
CXR chest X-ray Rheumatism
CYC cyclophosphamide FADD FAS-associated death domain
cysLT cysteinyl leukotrienes Fas type-II transmembrane protein of
DAD diffuse alveolar damage tumor necrosis factor family
DAMPS danger-associated molecular FcR fragment of constant region
patterns FcεRI high-affinity IgE receptor
 Abbreviations xxiii
FDA Food and Drug Administration HLA-E gene for HLA class I
FEV1 forced expiratory volume in the histocompatibility antigen, alpha
first second chain E
FFA free fatty acid HNP human neutrophil peptides
FGF fibroblast growth factor HR hazard ratio
FL follicular lymphoma HRCT high-resolution computed
FOXP3 forkhead box protein 3 tomography
FSH follicle-stimulating hormone HSCT hematopoietic stem cell
FVC forced vital capacity transplantation
GABA gamma-amino butyric acid HT Hashimoto’s thyroiditis
GALT gut-associated lymphoid tissue HVEM herpes virus entry mediator
GC germinal center B cells IADs inflammatory autoimmune
GCA giant cell arteritis diseases
GCF gingival crevicularfluid iBALT inducible bronchus-associated
GCM giant cell myocarditis lymphoid tissue
GCs germinal centers IBD inflammatory bowel disease
GCS glucocorticosteroid IBM inclusion body myopathy
G-CSF granulocyte colony-stimulating IBT immunobead test
factor IC immune-complex
GEF guanine nucleotide exchange factor ICAM-1 intercellular adhesion molecule-1
GITR glucocorticoid-induced tumor ICD implantable cardiac-defibrillator
necrosis factor receptor ICOS(L) inducible T-cell co-stimulator (ligand)
GITRL glucocorticoid-induced tumor ICs immune complexes
necrosis factor receptor ligand IDB inflammatory bowel diseases
GM-CSF granulocyte-macrophage colony- IDO indoleamine 2,3-dioxygenase
stimulating factor IEI inborn errors of immunity
GO gene-ontology IFN interferon
GoF gain of function Ig immunoglobulin
GPA granulomatosis with polyangiitis IgG4-RD’s IgG4 related autoimmune diseases
GPCR G-protein-coupled receptors IgM immunoglobulin M
GPCR-AABs G-protein-coupled receptors IgSF immunoglobulin superfamily
autoantibodies IIF indirect immunofluorescence
GPx glutathione peroxidase IIMs idiopathic inflammatory
GvHD graft-versus-host disease myopathies
GWAS genome-wide association studies IL interleukin
H2A histone 2A IL2RB gene for Interleukin 2 receptor
H2O2 hydrogen peroxide subunit beta
HAART high-active antiretroviral therapy ILC innate lymphoid cells
HBV hepatitis B virus ILD interstitial lung disease
HBV-PAN hepatitis B virus-associated infDCs inflammatory dendritic cells
polyarteritis nodosa INS gene for insulin
HCC hepatocellular carcinoma IPAF interstitial pneumonia with
hCG human chorionic gonadotropin autoimmune features (IPAF)
HCLO hypochlorousacid IPEX immunodysregulation,
HCV hepatitis C virus polyedocrinopathy, enteropathy,
HHV-6 human herpesvirus 6 X-linked
HIV human immunodeficiency virus IPF idiopathic pulmonary fibrosis
HL Hodgkin’s lymphoma irAEs immune-related adverse effects
HLA human leukocyte antigen IRIS immune reconstitution
HLA-DOB HLA class II histocompatibility inflammatory syndrome
antigen, DO beta chain ISGs interferon-stimulated genes
HLA-DR human leukocyte antigen-DR ITIM immunoreceptors tyrosine-based
isotype inhibitory motifs
xxiv Abbreviations

ITK interleukin-2-inducible MMP mucous membrane pemphigoid

T-lymphocyte kinase MMPs matrix metalloproteinases
ITP immune thrombocytopenic MPA microscopic polyangiitis
purpura MPN myeloproliferative neoplasms
IUIS International Union of MPO myeloperoxidase
Immunological Societies MR mitral regurgitation
IVF in vitro fertilization or MS multiple sclerosis
intracytoplasmic sperm injection mTECs medullary thymic epithelial cells
(ICSI)-embryo transfer (ET) mTOR mammalian target of rapamycin
IVIG intravenous immunoglobulin MUC5B gene encoding mucin 5B
JAK/STAT Janus kinase/signal transducers MxA myxovirus resistance protein1
and activators for transcription MZL marginal zone lymphoma
JIA juvenile idiopathic arthritis NA not available
K/BxN serum-transfer arthritis model in NADPH nicotinamide adenine dinucleotide
murine species phosphate
KD Kawasaki disease NAFLD non-alcoholic fatty liver disease
KL-6 Krebs von den Lungen 6 NET neutrophil extracellular trap
LA lupus anticoagulant NFAT nuclear factor of activated T cells
LAG-3 lymphocyte activation gene-3 NF-kB nuclear factor kappa-light-chain-
LAIR- 1 leukocyte-associated Ig-like enhancer of activated B cells
receptor NHL non-Hodgkin’s lymphoma
LCV leukocytoclastic vasculitis NIK NF-κB inducing kinase
LF lymphoid follicles NK natural killer cells
LIF leukemia inhibitor factor NKT natural killer T cells
LIP lymphocytic interstitial pneumonia NLRP3 NLR family pyrin domain-
LPS lipopolysaccharide containing 3
LRBA lipopolysaccharide-responsive NMDA N-methyl-d-aspartate
beige-like anchor protein NMDA-R NMDA receptors
lSSc cutaneous limited SSc NMOSD neuromyelitisoptica spectrum
LT leukotriene disorders
LTF lactoferrin NO nitric oxide
LVEF left ventricular ejection fraction NSAIDs nonsteroidal antiinflammatory
mAbs monoclonal antibodies drugs
MAC membrane attack complex NSCLC non-small cell lung cancer
MALT mucosa-associated lymphoid tissue NSIP nonspecific interstitial pneumonia
MAPK mitogen-activated protein kinase NVC nailfoldvideocapillaroscopy
MAR mixed agglutination reaction NYHA New York Heart Association
MBP major basic protein OD odds ratio
MCAF monocyte chemotactic and OLP oral lichen planus
activating factor OP organizing pneumonia
MCC merkel cell carcinoma OSADs organ-specific autoimmune diseases
MCL mantle cell lymphoma PA phosphatic acid
MCP monocyte chemoattractant protein PAD peptidyl arginine deiminase
MDA malondialdehyde PADSDA produce anti-double-stranded
MDSCs myeloid-derived suppressor cells DNA antibodies
MDT multidisciplinary team PAMPs pathogen associated molecular
MG myasthenia gravis patterns
MGUS monoclonal gammopathy of PAN polyarteritis nodosa
undetermined significance P-ANCA perinuclear antineutrophil
MHC major histocompatibility complex cytoplasmic antibody
MIF migration inhibition factor PARN poly(A)-specific ribonuclease
miRNA microRNA PARs protease-activated receptors
MM multiple myeloma PCMZL primary cutaneous marginal zone
MMF mycophenolate mofetil B-cell lymphoma
 Abbreviations xxv
PCOS polycystic ovary syndrome RNS reactive nitrogen species
PCP phencyclidine RORC2 retinoic acid-related-orphan
PCR polymerase chain reaction receptor-gamma splice variant
PD-1 programmed cell death protein 1 RORγt retinoic acid-related orphan
PD-1H programmed death-1 homolog receptor γt
pDC plasmacytoid dendritic cells ROS reactive oxygen species
pDCs plasmacytoid DCs RP Raynaud’s phenomenon
PDGF platelet derived growth factor RR risk relative
PD-L1 programmed death ligand 1 RSV respiratory syncytial virus
PE phosphatidylethanolamine RTX rituximab
PG phosphatidylglycerol RUNX3 gene of Runt-related transcription
PI phosphatidylinositol factor 3
PI3Kδ δ subunit of phosphatidylinositol 4, RV rhinovirus
5 diphosphate 3 kinase SADs systemic autoimmune diseases
PIDD primary immunedeficiency SAMHD1 SAM and HD domain-
disorders containing deoxynucleoside-
PIMs proinflammatory mediators triphosphohydrolase 1
PIRD primary immuneregulatory SAVI sting-associated vasculopathy with
disorders onset in infancy
PKB protein kinase B SCCHN squamous cell carcinoma of the
PM polymyositis head and neck
PM particular matters SCID severe combined
PMR polymyalgia rheumatica immunodeficiency
PNS paraneoplastic syndrome Scl-70 scleroderma antibodies
POF premature ovarian failure SCLC small-cell lung cancer
POLD DNA polymerase delta SE shared epitope
PPL periplakin Se selenium
PPRs pattern recognition receptors SFTPC surfactant protein C
PR3-ANCA ANCA against proteinase 3 SIgAD selective IgA deficiency
PRRs pattern recognition receptors SIgMD selective IgM deficiency
PRTN transcription regulatory protein SIR standardized Incidence Ratio
PS phosphatidylserine SjS Sjögren’s syndrome
pSS primary Sjӧgren’s syndrome SLE systemic lupus erythematosus
PTC papillary thyroid cancer SMC smooth muscle cell
PV pemphigus vulgaris SMR standardized mortality ratio
PYHIN1 gene of pyrin and HIN domain SNP single-nucleotide polymorphism
family member 1 SOCS3 secretion of cytokine signaling 3
QoL quality of life SOD superoxide dismutase
RA rheumatoid arthritis SPENCD Spondyloen chrondro-dysplasia
RAG1/2 recombination-activating SS systemic sclerosis
gene 1/2 SSD scleroderma spectrum disorder
RAS recurrent aphthous stomatitis ssDNA single-stranded DNA
RAS/MAPK rat sarcoma/mitogen-activated ST2 suppression of tumorigenicity 2
protein kinase STAT signal transducer and activator of
RCC renal cell carcinoma transcription
R-CHOP rituximab-cyclophosphamide- STK4 serine/threonine kinase 4
doxorubicin-vincristine- T1D type 1 diabetes mellitus
prednisolone T2D type 2 diabetes
RCT randomized controlled trial TA takayasu arteritis
RETL1 rearranged during transfection TAAs tumor-associated antigens
ligand 1 TACI transmembrane activator and
RF rheumatoid factor calcium-modulator and cyclophilin
RHD rheumatic heart disease ligand interactor
RICD restimulation-induced cell death TAMs tumor-associated macrophages
xxvi Abbreviations

TAP1/2 transporter associated with antigen TREC T-cell receptor excision circles
processing ½ Treg T regulatory cells
TBA thiobarbituricacid TSA tissue-specific antigens
TBARS thiobarbituric acid reacting TSAb thyroid-stimulating antibody
substances TSH thyroid-stimulating hormone
TCL T-cell lymphoma TSLP thymic stromal lymphopoietin
TCR T-cell receptor U.S. FDA United States Food and Drug
TCZ tocilizumab Administration
tDCs tolerogenic dendritic cells UA uric acid
TERT telomerase reverse transcriptase UIP usual interstitial pneumonia
Tfh T follicular helper cells uNK uterine NK
TgAbs antibodies to thyroglobulin UV ultraviolet
TGF-β tumor growth factor-β VAT visceral adipose tissue
TGF-β transforming growth factor-beta VC vital capacity
Th T-helper VCAM-1 vascular cell adhesion molecule-1
TIGIT T-cell immunoreceptor with Ig and VECTOR VElcro Crackles detecTOR
ITIM domains VEGF vascular endothelial growth factor
TILs tumor-infiltrating lymphocytes VISTA V-domain Ig suppressor of T cell
TIM T cell Ig and mucin domain activation
TIM-3 T cell immunoglobulin-3 WAS Wiskott-Aldrich syndrome
TIMP tissue inhibitor of matrix WAT white adipose tissue
metalloproteinase WHF World Heart Federation
TKI tyrosine kinase inhibitor WHO World Health Organization
TLR toll-like receptor WT wild type
TME tumor microenvironment XLA X-linked agammaglobulinemia
TNF tumor necrosis factor ZAP-70 zeta-chain associated protein
TNFRSF tumor necrosis factor receptor kinase 70
superfamily ZP zona pellucida protein
TPE therapeutic plasma exchange α2-HS alpha 2 Heremans Schmidt
TPOAbs antibodies to thyroperoxydase αSMA alpha smooth muscle actin
thyroperoxidase β2-AAbs β2-adrenergic receptor autoantibodies
Tr1 Tregs producing IL-10 β2GPI β2 glycoprotein I
TRC T-cell receptor
 C H A P T E R

1
Introduction on autoimmunity
and associated conditions
Nima Rezaeia,b,d,* and Niloufar Yazdanpanaha,c,d
a
Research Center for Immunodeficiencies, Children's Medical Center, Tehran University
of Medical Sciences, Tehran, Iran bDepartment of Immunology, School of Medicine, Tehran
University of Medical Sciences, Tehran, Iran cSchool of Medicine, Tehran University of Medical
Sciences, Tehran, Iran dNetwork of Immunity in Infection, Malignancy and Autoimmunity
(NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
⁎
Corresponding author

Abstract
Autoimmunity has been reported in association with a broad spectrum of conditions. With regard to the
burden imparted by autoimmune diseases on patients and the healthcare system due to the chronic nature of
the disease, the absence of a definite cure, and the potential comorbidities, associated conditions with autoim-
munity are of high significance and should be studied. For instance, autoimmune manifestations have been
reported in infections, genetic syndromes, inborn errors of immunity (IEI), malignancies, metabolic disorders,
and other medical conditions that could potentially affect patients’ quality of life (QoL). Indeed, the associ-
ation of autoimmunity in most of these conditions has been proved to be bidirectional, since autoimmunity
could lead to development of majority of these conditions, while autoimmune manifestations could develop
in the context of the aforementioned conditions as well.

Keywords
Autoimmunity, Immunodeficiency, Cancer, Metabolic diseases, Infection

1 Introduction

Autoimmune diseases are associated with a broad spectrum of medical conditions, which
could be attributed to the multifactorial and unknown etiology of autoimmune diseases.
Autoimmune diseases emerge at different ages, from the very first days of life to the elderly.

Translational Autoimmunity, Vol. 3 1 Copyright © 2022 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/B978-0-323-85415-3.00009-X
 1. Introduction on autoimmunity and associated conditions

Autoimmune manifestations have been reported in genetic syndromes and inborn errors of
immunity (IEI), which are chiefly diagnosed in the early years of life. Although advances
in diagnostic methods have facilitated and accelerated the diagnosis at earlier stages of the
disease, and novel therapeutic strategies have successfully reduced the complications of the
disease, the associated autoimmune manifestations could persist even after receiving proper
treatment. Therefore, it imposes a remarkable burden on individuals, families, health-care
services, and society.
There is a mutual association between malignancy and autoimmunity. The paraneoplastic
syndrome is known as an accompanying condition to malignancies, which occurs following
abnormal anticancer immune responses that target the normal tissues of the body. On the
other hand, the risk of some specific types of malignancies is potentially higher in patients
with autoimmune diseases. The latter could be attributed either to the overall inflammatory
state, which is dominant in autoimmune patients, or to the immunosuppressive/immuno-
modulatory effects of medications prescribed for autoimmune diseases.
In addition, infections have been long known as one of the most important triggering fac-
tors of autoimmunity. Since infections, opportunistic infections in particular, are reported as
an adverse effect of autoimmune treatments, a bidirectional association could be hypothe-
sized in this context as well.
Besides all the above-mentioned associations, autoimmune diseases could be associated
with comorbidities that affect patients’ quality of life (QoL). For instance, obesity, infertil-
ity, stress and mental complications are some of the main factors influencing patients’ QoL.
Hence, highlighting the associations and comorbidities of autoimmune diseases might lead
to better management of patients and potentially attenuate the severity of associated condi-
tions. This chapter aimed to provide a comprehensive overview of the current literature on
autoimmunity and associated conditions.

2 Autoimmunity and infection

Classically, it was widely accepted that infections trigger autoimmunity and rheumatic
fever has been recognized as the most well-known example of conditions that is triggered
by infectious agents (group A beta-hemolytic streptococcus) [1]. Several mechanisms have
been proposed to explain infection-induced autoimmunity, which are dependent on the
breakdown of tolerance, such as molecular mimicry, polyclonal activation, epitope spread-
ing, and bystander activation [2]. However, the role of infections on autoimmune diseases
has extended from a triggering factor to an inhibiting factor. For instance, inflammatory
bowel disease (IBD) is reported to be attenuated in patients with helicobacter pylori infec-
tion [3, 4]. “Hygiene hypothesis,” which was initially stated by Strachan in 1989 [5], has
been suggested to rationalize the protective effect of infections in autoimmune diseases
[6, 7]. Preclinical observations and reports of animal studies further support the protec-
tive and ameliorative role of infections in autoimmune diseases. For instance, Bordetella
pertussis infection results in the production of IL-10, an antiinflammatory mediator, which
is claimed to be responsible for the protective effect of this bacterial infection on multiple
sclerosis (MS) patients [8]. Hepatitis B virus, Epstein-Barr virus (EBV), Coxsackieviruses
group B, lymphocytic choriomeningitis virus, Klebsiella pneumonia, Helicobacter pylori, and

2
Another random document with
no related content on Scribd:
Mad Tom in A Rage A CONTEMPORARY CARTOON TYPICAL OF THE
FEDERALIST ATTACKS ON JEFFERSON

‘Aurora.’[1524] These were minor incidents—the background for the real

terror to come. Judges were terrorizing the people with wild charges to grand
juries.[1525] The Right Reverend Bishop White of Philadelphia was
preaching piously and patriotically from the text: ‘Let every soul be subject
to the higher powers. For there is no purpose but of God. The powers that be
are ordained of God. Whoso therefore resisteth the power, resisteth the
ordinance of God. And they that resist shall receive to themselves
damnation.’[1526] The Administration organ in New York was laying down
the dictum: ‘When a man is heard to inveigh against the Sedition Law, set
him down as one who would submit to no restraint which is calculated for
the peace of society. He deserves to be suspected.’[1527] And Timothy
Pickering was nervously peering through his spectacles over Jeffersonian
papers seeking some phrase on which a prosecution for sedition could be
brought, and prodding the district attorneys to action. ‘Heads, more heads!’
screamed Marat from his tub. ‘Heads, more heads!’ echoed Pickering from
his office.
 CHAPTER XVII

THE REIGN OF TERROR

I T is not surprising that the first notable victim of the Terror was Matthew
Lyon whom we have seen insulted at various points when homeward
bound from Philadelphia. Bitter though he was, he had sound sense and
realized his danger. When the Rutland ‘Herald’ refused to publish his
address to his constituents, he launched his own paper, ‘The Scourge of
Aristocracy,’ with a defiant challenge: ‘When every aristocratic hireling
from the English Porcupine ... to the dirty hedge-hogs and groveling animals
of his race in this and neighboring States are vomiting forth columns of lies,
malicious abuse and deception, the Scourge will be devoted to politics.’
How Pickering must have stared through his spectacles at that defiance! But
patience! If speeches and papers offered no case, there still were letters, and
one was found. Here surely was ‘sedition.’ Had Lyon not referred to
Adams’s ‘continual grasp for power,’ to his ‘unbounded thirst for ridiculous
pomp, foolish adulation, and selfish avarice’? Had he not charged that the
President had turned men out of office for party reasons, and that ‘the sacred
name of religion’ was ‘employed as a state engine to make mankind hate and
persecute one another’? Had he not printed a letter from Barlow, the poet,
referring to ‘the bullying speech of your President and the stupid answer of
your Senate’? It was enough. True, the letter had been published before the
Sedition Law was passed, but this was the Reign of Terror. The trial before
Judge Peters was a farce, and the culprit was found guilty. ‘Matthew Lyon,’
said Peters in fixing the sentence, ‘as a member of the Federal Legislature
you must be well acquainted with the mischiefs which flow from the
unlicensed abuse of Government’—and Lyon was sentenced to four months
in jail and to pay a fine of a thousand dollars.
Then the Terror began to work in earnest. There was a fairly respectable
jail at Rutland where the trial was held, but not for Lyon. There was
something worse at Vergennes, forty miles away, a loathsome pen in a
miserable little town of sixty houses, and thither he was ordered. Refusing
his request to return to his house for some papers, he was ordered to mount a
horse, and with two troopers with pistols, riding behind, the forty-mile
journey through the wilderness was made. At Vergennes they pushed him
into a cell, sixteen by twelve, ordinarily used for common felons of the
lowest order. In one corner was a toilet emitting a sickening stench. A half-
moon door opened on the corridor, through which his coarse food was
passed. Through a window with heavy iron bars he got some light. There
was no stove and the cold of autumn nights came in through the window.
When it became dangerously chilly, the prisoner put on his overcoat and
paced the cell. He was refused pen and paper until the indignation of the
public forced a concession. A visitor peering through the half-moon of the
door a little later would have seen a table strewn with paper, Volney’s
‘Ruins,’ some Messages of the President.
Meanwhile the Vermont hills were aflame with fury. The Green Mountain
Boys, the Minute Men, the soldiers who, with Lyon, had followed Ethan
Allen, were talking of tearing the jail down. Then, from the filthy, foul-
smelling hole, into which the Federalists had thrown a member of Congress,
came letters from the ‘convict,’ brave, cheerful letters, exhorting these men
to observe the law. One day, however, Lyon was forced to plead through the
iron bars of his window for the furious mob without to seek redress legally at
the polls. Thus popular resentment increased with the growth of the
prisoner’s popularity. Thousands of the yeomanry of Vermont signed a
petition for a pardon and sent it to Adams, who refused to receive it. Aha,
‘the despicable, cringing, fawning puppy!’ exulted Fenno.[1528] The
indignation of the yeomanry of Vermont now blazed high. The
Administration was amazed, almost appalled. When this ‘convict’ in a
hideous cell was nominated for Congress, there were not jails enough in
Vermont for the talkers of ‘sedition.’ He was elected overwhelmingly with
4576 votes to 2444 for his nearest competitor.
Again the terrorists consulted on plans to thwart the public will. His term
was about to expire, but where would this pauper get a thousand dollars?
True, the farmers, the comrades of the Revolution, were going into their
pockets to get the money—but a thousand dollars! Still there was a chance.
The Marshal summoned Federalist lawyers to go over Lyon’s letters and find
more sedition on which he could be arrested on emerging from the jail. His
triumphant election was more than the terrorists could bear. ‘Must our
national councils be again disgraced by that vile beast?’ asked their New
York organ.[1529] Meanwhile, the problem of the fine was being solved. The
eyes of the Nation were on that dirty little cell at Vergennes. Jefferson,
Madison, Gallatin, John Taylor of Caroline, Senator Mason of Virginia—he
who had given the Jay Treaty to the ‘Aurora’—and Apollis Austen, a
wealthy Vermont Democrat, were solving the problem of the fine. On the
day of Lyon’s delivery, the Virginia Senator rode into the village, his saddle-
bags bulging with a thousand and more in gold. There he met Austen with a
strong-box containing more than a thousand in silver. Mason paid the
money.
Before the jail had assembled a vast multitude. Out of the door rushed
Lyon. ‘I am on my way to Philadelphia!’—to Congress, he shouted. A roar
went up, a procession with a flag in front was formed, and the ‘convict’ was
on his way triumphantly. The school children at Tinmouth paraded in his
honor, and a youthful orator greeted him with a welcome to ‘our brave
Representative who has been suffering for us under an unjust sentence, and
the tyranny of a detested understrapper of despotism.’ The woods
reverberated with shouts. Then on moved the procession. At Bennington,
another ovation, more speeches. Seated in a sleigh, his wife beside him,
Lyon was escorted by the throng. At times the procession was twelve miles
long. Through New York, New Jersey, Pennsylvania, the ovations were
repeated. He had gone home to the tune of ‘The Rogue’s March’; he returned
by the same route to the tune of ‘Yankee Doodle.’[1530]

II

The terrorists ground their teeth and sought revenge—with nothing too
petty. The Reverend John C. Ogden dared to be a Democrat and to carry the
petition for Lyon to Philadelphia. Thenceforth he was a marked man. He was
in debt—and a debt would serve. Returning from Philadelphia, he was
arrested at Litchfield, Connecticut, and thrown into jail. ‘It is presumed,’
sneered Major Russell of the Boston ‘Centinel,’ ‘that Lyon when he goes
from his jail to Congress will at least sneak into Litchfield to pay a visit to
his envoy and take a petition from him to the Vice-President
[Jefferson].’[1531] But jail was too good for such a rascal. On his release a
crowd of soldiers followed him out of Litchfield, calling him ‘a damn
Democrat,’ abusing, insulting, collaring, shaking him. It was their purpose to
take him back to Litchfield and scourge him in public. Whirling him around,
the gallant soldiers started back. Meanwhile, the report had spread that the
heroic remnant of the army had set forth on a mobbing expedition, and a
party of Democrats and civilians mounted horses and rushed to the rescue.
The courage of the soldiers, so splendid in the presence of one man, oozed
out on the approach of the rescuers, and Ogden was released.[1532]

III

But Ogden was not the only victim of the terrorists, among the friends of
Lyon. Anthony Haswell, born in England, a man of education, who had seen
service in the army of Washington and had narrowly escaped death at
Monmouth, was editor of the ‘Vermont Gazette.’ A gentleman of amiability
and integrity, his popularity was great in Vermont—but he was a
Jeffersonian. One day the sleuths of the Terror, scanning the pages of
Democratic papers, found an appeal in Haswell’s ‘Gazette’ for funds to pay
the fine of Lyon. It referred to the ‘loathsome prison,’ to the marshal as ‘a
hard-hearted savage, who has, to the disgrace of Federalism, been elevated
to a station where he can satiate his barbarity on the misery of his victims.’ It
was a faithful portrait. But in concluding, the article charged that the
Administration had declared worthy of the confidence of the Government
the Tories ‘who had shared in the desolation of our homes and the abuse of
our wives and daughters.’
Thus, one night there was a hammering on the door of Haswell’s house,
and he was confronted by petty officials and notified to prepare for a journey
to Rutland in the early morning. In feeble health, and unaccustomed to
riding, he was forced to mount a horse for the sixty-mile ride to the capital.
Through a cold October rain the sick man jolted along in misery through the
day, and it was near midnight when the town was reached. With his clothing
soaked, he begged permission to spend the night at a hotel where he could
dry it. This was curtly refused. At midnight they pushed the sick man in wet
clothing into a cell. Responsible men of Rutland begged permission to go
security to the end that the editor might spend the night in decent quarters—
it was denied. The next morning he was hurried to trial at Windsor before
Judge Paterson who, on the Bench, continued to be a New Jersey politician.
The defense introduced evidence to prove the charge of brutality against the
marshal, and asked the Court for permission to summon McHenry and
General Drake of Virginia to prove that on one occasion the Administration
had acknowledged the policy of occasionally appointing Tories to office.
The Court refused permission; and having refused, Paterson declared in the
charge that ‘no attempt had been made at justification’ of the reference to
Tories. The jury was probably packed. The verdict was promptly rendered—
guilty of sedition. And Haswell was sent to jail for two months. On the day
of the expiration of his sentence, a great throng assembled at the prison to
testify to their regard for Haswell and their contempt for the Sedition Law
and its sponsors. When the editor appeared at the door, the band played
while the crowd sang:

‘Yankee Doodle, keep it up,

Yankee Doodle dandy.’

It was all too evident that, despite the Sedition Law, there were ‘Yankee
Doodles’ to ‘keep it up’ too numerous for the jails.

IV

The enforcement of the law in Massachusetts offered comedy, tragedy,

and farce—with at least one hero among the victims. There was something
of pathos even in the farce. An illiterate and irresponsible soldier of the
Revolution, David Brown, was wandering about the country reading and
distributing some foolish compositions of his own that were
incomprehensible in their incoherency. It was possible to detect some
dissatisfaction with the Administration, however. His was the grievance of
many others of the ragged Continentals of the ranks. He was a Democrat.
Fisher Ames, who was not a soldier, though old enough to have been one,
was outraged and alarmed over the foolish fellow’s activities, and pretended
to believe that he was one of the Jeffersonian ‘runners sent everywhere to
blow the trumpet of sedition.’ He wrote Gore, who had grown rich buying
up the paper of the private soldiers, of this ‘vagabond ragged fellow, who
lurked about in Dedham telling everybody the sins and enormities of the
government.’ Ames understood that he ‘knew of my speculating connection
with you;[1533] and how I had made my immense wealth.’[1534] Finally he
participated in the erection of a liberty pole at Dedham bearing among its
inscriptions the sinister words, ‘No Stamp Tax, No Sedition.’ The authorities
pounced upon him as legitimate prey.
The next scene was laid in the courtroom in Boston. On the Bench sat the
fat, red-faced Chase, like an avenging angel who looked too often on the
wine when it was red. It was solemnly proved that Brown had writings of his
own hostile to the Administration policies; that he had paid to have the
inscription painted for the pole at Dedham; and that in the presence of forty
or fifty dangerous farmers he had been seen holding the ladder while another
ascended to nail the board on. There was no defense. Chase glowered on the
miserable illiterate, and, reminding him that he was at the mercy of the
Court, demanded the names of the miscreants who had subscribed to his
writings. Brown refused to betray the imaginary men higher up, and Chase
fined him four hundred dollars and sent him to jail for a year and a half.
Working entirely on his own initiative, the unhappy wretch was buried in a
cell and all but forgotten. The Federalist papers recorded his conviction with
gusto, albeit with sorrow that such things could be. After sixteen months, he
sent a pitiful petition to Adams asking for a pardon, but it was refused. In
February, 1801, he sent a second petition, which was ignored. After
spending two years in a cell, he was pardoned by Jefferson.[1535] This trial
was a farce.

Followed then the comedy. Among the desperate characters who had
assisted in the pole-raising at Dedham was Richard Fairbanks. A thoroughly
decent citizen, he was arrested and dragged tremblingly into court. Most of
the victims of the Sedition Law were unrepentant and defiant, but Fairbanks
was full of remorse. There may have been a bit of cunning in his confession
of past wickedness and his profession of conversion. At any rate, the scene
in court was not so threatening. True, the stern-faced Chase looked down
from the Bench, but there in the room, ready to plead for mercy, was Fisher
Ames. The charge was read, confessed, and up rose Ames. Not, however, as
a paid attorney did he appear, but there was something to be said in
extenuation for Fairbanks. He realized ‘how heinous an offense it was.’ He
had promised to be a good citizen in the future. ‘His character has not been
blemished in private life,’ the orator said, ‘and I do not know that he is less a
man of integrity and benevolence than others. He is a man of rather warm
and irritable temperament, too credulous, too sudden in his impressions.’ He
had been seduced by the ‘inflammatory sophistry’ of the illiterate Brown.
‘Besides,’ continued Ames, in his most virtuous tones, ‘men in office have
not been wanting to second Brown and to aggravate the bad opinion of the
government and the laws.... The men who had Mr. Fairbanks’ confidence
and abused it are more blameable than he. A newspaper has also chiefly
circulated there which has a pestilent influence.’ Thus he had bad advice.
‘Although Mr. Fairbanks was influenced like the rest and was criminal in the
affair of the sedition pole he had no concern in the contrivance. He ... has
freely confessed his fault and promised to be in future a good citizen.’
Having attacked the Jeffersonians in Congress and out, and denounced ‘The
Aurora’ or ‘Independent Chronicle,’ and implied that Fairbanks would vote
and talk right in the future, Ames sat down; and just as solemnly Chase,
commenting that ‘one object of punishment, reformation, has been
accomplished,’ fined him five dollars and sent him to jail for six hours.
Whereupon we may imagine Chase and Ames felicitating themselves on
having scared the Democratic and Jeffersonian devils out of one sinner.
This was comedy.

VI

The tragedy in Massachusetts was reserved for a more important person

—the editor of the ‘Independent Chronicle,’ Thomas Adams, who was
printing one of the most powerful Jeffersonian papers in the country. He had
published an attack on the denunciation of the Virginia Resolutions by the
Massachusetts Legislature.[1536] The Essex Junto had been seeking a chance
at the throat of the editor. His paper had been keenly searched for some
excuse for action under the Sedition Law. In the autumn of 1798 he had been
arrested and the effect had been provoking. In announcing his arrest, Adams
had promised his readers a full report of the trial, and pledged himself to
‘always support the rights of the people and the liberty of the press,
agreeable to the sacred charter of the Constitution.’[1537] When, four days
later, he reported the postponement of his trial, he was able to ‘thank our
new subscribers whose patriotism has led them to support the freedom of the
press since the late persecution.’[1538]
The political persecution of Adams had in no wise intimidated him.
Every issue of his paper was a clarion call to the faithful. If anything, he
raised his banner a little higher. The public, looking upon his arrest as
tyrannical and outrageous, rallied around him as never before. Eleven days
after his arrest, he reported an ‘unprecedented increase in circulation,’ and
pledged himself to carry on the fight. Not without point did he quote, ‘A free
press will maintain the majesty of the people,’ for, as he explained, ‘this was
originally written by John Adams, President of the United States, for Edes
and Gill’s Boston Gazette when British Excises, Stamp Acts, Land Taxes,
and Arbitrary Power threatened this country with poverty and
destruction.’[1539] Courageous though he was, the persecution drained the
editor’s weakened vitality, and he was confined to his bed in a country house
near Boston when the attack on the Massachusetts Legislature was
published. Though too ill to be dragged into court, he was not too ill to
announce the second phase of the persecution in the language of defiance.
Double-spacing the announcement to make it stand out like a challenge, he
said: ‘The Chronicle is destined to persecution.... It will stand or fall with the
liberties of America, and nothing shall silence its clarion but the extinction
of every principle which leads to the achievement of our
independence.’[1540] Because the editor could not be dragged from a sick
bed, Abijah Adams, the bookkeeper, was arrested on the ground that he had
sold the papers and therefore published the ‘libel.’
Chief Justice Dana presided at the trial—as intolerant, politically, but not
as stupid and coarse as Chase. The prosecution based its action on the
common law of England, which the defense declared inconsistent with the
Constitution of Massachusetts, and hostile to the spirit of the American
Government. Dana rose to the occasion, not only attacking Adams’s lawyers
from the Bench, but assailing them through the press.[1541] The result was
inevitable. A verdict of guilt was promptly reached, and Dana made the most
of his opportunity in sentencing the criminal. The defendant’s lawyers were
denounced for ‘propagating principles’ as ‘dangerous as those of the article
on which the indictment was based.’ Since the editor would not give up the
name of the author of the offensive article, Adams would have to suffer, and
he was sentenced to jail for thirty days, ordered to pay costs, and to give
bond for good behavior for a year. So shocking was the spirit of Dana in
passing sentence that he was challenged in the ‘Chronicle’ to publish his
speech.[1542] Adams editorially denounced the application of the common
law of England as ‘inconsistent with republican principles contemplated and
avowed in our Constitution, and inapplicable to the spirit and nature of our
institutions,’[1543] and promised ‘a regular supply of the papers.’ ‘The Editor
is on a bed of languishment, and the bookkeeper in prison, yet the cause of
liberty will be supported amid these distressing circumstances.’
The ‘convict’ was hurried off to jail, and into a damp, unhealthy cell
where his feeble constitution threatened to succumb, until an indignant
protest from without forced the jailer to transfer him to a better. The friends
who flocked to see him were forced to convey their consolations through
double-grated doors. Day by day the paper went to press, its spirit not one
whit diminished. With the editor sinking under disease and the anticipated
wreckage of his property, and the bookkeeper sick in jail and distressed over
the condition of his wife and children, the fight was waged with
undiminished vigor.[1544] One day old Samuel Adams, his Revolutionary
spirit ablaze, flaunted his respect for the editor and his contempt for the
persecutors, by stalking to the jail and expressing his admiration through the
bars.[1545] That day Adams’s prison doors were opened and he passed out to
freedom; and the next day the readers of the ‘Chronicle’ knew that ‘Abijah
Adams was discharged from his imprisonment after partaking of an adequate
portion of his “birth-right” by a confinement of thirty days under the
operation of the common law of England.’[1546] Within three weeks,
Thomas Adams, one of the bravest champions of democracy and the
freedom of the press, was dead—his end hastened by the persecution to
which he had been subjected. Like Benjamin Franklin Bache, he sank into
his grave with an indictment under the Sedition Law hanging over him.

VII

When Bache thus escaped the vengeance of his enemies, they turned to
his successor, William Duane, who soon proved himself a more vigorous
controversialist than his predecessor. A remarkable character was Duane,
entitled to a monument for his fight for the freedom of the press. Born in
America of Irish parentage, he was taken to Ireland on the death of his
father, and there he grew to manhood. His career previous to his return to
America was colorful and courageous. For a time he had been a reporter for
the London ‘Times’ in the press gallery of the House of Commons, before
establishing a newspaper in India which he edited with such signal ability
that the East India Company found it advisable to resort to force and fraud to
destroy his property and send him out of the country. At length in sheer
disgust he returned to America, and soon became the editor of ‘The
Aurora.’[1547]
One Friday night before the Monday on which the question of the repeal
of the Alien Law was to be considered in Congress, a number of citizens,
including some foreign-born, met in Philadelphia to arrange for a memorial
to Congress. On Sunday morning, Duane and three others, including Dr.
James Reynolds, appeared during services in the churchyard of Saint Mary’s
Catholic Church with the memorial and a few placards requesting natives of
Ireland in the congregation to remain in the yard after the services to sign the
petition. Some of these placards were placed on the church and on the gates
leading into the yard. Some belated worshipers of the Federalist persuasion
tore these down, and, entering the church, warned the priest that seditious
men were in the yard planning a riot. The four men in the yard conducted
themselves with perfect decorum. When the congregation was dismissed,
Duane and his party had the memorial spread upon a tombstone. A few
approached and signed. Almost immediately, however, the terrorists among
the members of the church closed in upon the group, centering their attacks
mostly upon Reynolds, who was knocked down and kicked. Struggling to
his feet, Reynolds drew a revolver and prepared to defend himself, at which
moment officers reached the scene and the four men were hurried off to jail
on the charge of creating a seditious riot.
Before a great crowd at the State House, the trial was held, with
Hopkinson, the author of the war song, as special prosecutor, and the men in
the dock brilliantly defended by A. J. Dallas. The testimony showed that
there had been no disturbance until the mob charged upon the men with the
memorial; that the memorial itself was unexceptionable in every way; that
Reynolds had been warned a week before of a conspiracy to murder him and
had armed himself on advice of a member of Congress; that none of the
others carried a weapon of any sort; and it was shown by the testimony of a
priest that it was then the custom in Ireland to post notices in churchyards,
and for members of the church to transact such public business in the yards
after services. Members of the congregation testified that they had wanted to
sign; the priest that the posting of the notice was not considered disrespectful
to the church. In a brilliant speech of sarcasm and invective, Dallas riddled
the prosecution, calling attention to attempts to intimidate lawyers from
appearing for the defense, charging the prosecution with being inspired by
partisan hate, and denouncing the Alien Law. Hopkinson replied lamely,
attacking immigrants and Democrats. The jury retired, and in thirty minutes
returned with a verdict of acquittal. The State House rang with cheers. The
case, however, had not been tried in a Federal Court.[1548]
That, however, was only the beginning of the attempt to wreck and ruin
the leading Jeffersonian editor. John Adams and Pickering had been
planning to reach him by hook or crook. The latter wrote Adams that Duane,
though born in America, had gone to Ireland before the Revolution; that in
India he ‘had been charged with some crime’; and that he had come to
America ‘to stir up sedition.’ More—he was ‘doubtless a United Irishman,’
and in case of a French invasion the military company he had formed would
join the invaders. The picture was as Adams would have had it painted. ‘The
matchless effrontery of Duane,’ he wrote, ‘merits the execution of the Alien
Law. I am very willing to try its strength on him.’ This trial was never made,
but two months later the Federal Courts began to move against him. At
Norristown, Pennsylvania, with Bushrod Washington and Richard Peters on
the Bench, an indictment was brought against him for sedition.[1549] The
case was continued until June, 1800—and Duane went full steam ahead with
his attacks on the Federalist Party. The trial was again postponed, and in
October, 1800, he was indicted again—this time for having published a
Senate Bill of a peculiarly vicious if not criminal character which its
sponsors for sufficient reasons wished kept from the public. But it was of no
avail. He would not cringe or crawl or compromise or be silenced. The cases
against him were dismissed when Jefferson became President. Many
historians have belittled him; he fought brilliantly for fundamental
constitutional rights when men high in office, who are praised, were
conspiring to strike them down.

VIII

One day the Sedition snoopers fell upon an article by Dr. Thomas Cooper,
an Englishman by birth, a scientist and physician by profession, a man of
learning and culture, and a Jeffersonian. It referred to the early days of
Adams’s Administration when ‘he was hardly in the infancy of political
mistake.’ It charged Adams with saddling the people with a permanent navy;
with having borrowed money at eight per cent; referred to his ‘unnecessary
violence of official expression which might justly have provoked war’; to his
interference with the processes of a Federal Court in the case of Robbins.
And that was all. Adams had made mistakes, had established a permanent
navy, had borrowed money at eight per cent; and many thought at the time
that he had unduly interposed in the Robbins case. But this was sedition in
1800.
Hustled into the Federal Court at Philadelphia, Cooper found the red-
faced Chase glowering upon him from the Bench—the same Chase who had
been charged by Hamilton with speculating in flour during the Revolution.
There was no denial of the authorship of the article. The evidence in, Chase
charged the jury in his most violent partisan manner. There are only two
ways to destroy a republic, he said: one the introduction of luxury, the other
the licentiousness of the press. ‘The latter is more slow but more sure.’
Taking up the Cooper article, he analyzed it in the spirit of a prosecutor.
Here, thundered the Judge, we have the opinion that Adams has good
intentions but doubtful capacity. Borrowed money ‘at eight per cent in time
of peace?’ What—call these times of peace? ‘I cannot suppress my feeling at
this gross attack upon the President. Can this be true? Can you believe it?
Are we now in time of peace? Is there no war?’[1550] The jury promptly
returned a verdict of guilty. The next day Cooper appeared for sentence.
Asked by Chase to explain his financial condition as that might affect the
sentence, he replied that he was in moderate circumstances, dependent on his
practice, which would be destroyed by imprisonment. ‘Be it so,’ he
continued. ‘I have been accustomed to make sacrifices to opinion, and I can
make this. As to circumstances in extenuation, not being conscious that I
have set down aught in malice, I have nothing to extenuate.’ Chase became
suspiciously unctuous and oily. If Cooper had to pay his own fine, that
would be one thing; if his party had arranged to pay the fine, that would be
another. ‘The insinuations of the Court are ill founded,’ Cooper replied with
indignation, ‘and if you, sir, from misapprehension or misrepresentation,
have been tempted to make them, your mistake should be corrected.’ Judge
Peters, who had been squirming through these amazing partisan comments
of Chase, here impatiently intervened with the comment that the Court had
nothing to do with parties. Whereupon Cooper was fined a thousand dollars
and ordered to jail for six months.[1551]
Duane instantly announced an early publication in pamphlet form of the
trial in full. ‘Republicans may rest completely assured,’ he wrote, ‘that they
will have every reason to be satisfied with the effect of this most singular
trial on the mind of the public.’[1552] The pamphlet appeared, and, as Duane
had foreseen, the public was aroused. A man of decent character and high
professional standing was languishing in a jail in the capital of the country
for having told the truth and expressed an opinion on a constitutional
question. There were rumblings and grumblings in the streets, and some
uneasiness in Administration circles. The hint went forth that an appeal for a
pardon might receive consideration, and one was put in circulation, when out
from the ‘convict’s’ cell came a letter of protest. He wanted and would have
no petition for pardon. He believed with Adams that repentance should
precede pardon[1553] and he had no feeling of repentance. ‘Nor will I be the
voluntary cat’s-paw of electioneering clemency,’ Cooper continued. ‘I know
that late events have greatly changed the outward and visible signs of the
politics of the party, and good temper and moderation is the order of the day
with the Federalists now, as it has always been with their political opponents.
But all sudden conversions are suspicious, and I hope that Republicans will
be upon their guard against the insidious or interested designs of those who
may wish to profit by the too common credulity of honest intention.’[1554]
The petition was dropped. Cooper remained happily in his cell. His
incarceration was making votes for Jefferson. When, on the expiration of his
sentence, Cooper stepped into the daylight, he found a deputation of his
friends awaiting him at the door. He was escorted to a fashionable hotel
where a public dinner had been arranged to honor him and express contempt
for the Sedition Law. Two long tables were set, with Dr. James Logan
presiding over one, Thomas Leiper over the other. That night, as the wine
flowed, the men who would not be silenced drank to Cooper—to Jefferson—
to a Democratic victory.[1555]

IX

Having distinguished himself as an American Lord Clare in the case of

Cooper, Chase proceeded southward, boasting along the way that he ‘would
teach the lawyers in Virginia the difference between liberty and
licentiousness of the press.’ He was going to try James Thomas Callender
for sedition on an indictment based on his pamphlet, ‘The Prospect Before
Us.’ This unsavory creature was hated quite as much for the truths he told as
for the lies he circulated, and there was nothing in the section of his
pamphlet on which he was indicted to shock any one to-day. It was an attack
on Adams in connection with the French war hysteria, the navy, the army,
the Robbins case. The only phrase that startles one to-day is the reference to
the hands of Adams ‘reeking with the blood of the poor friendless
Connecticut sailor.’[1556] The scenes in the little Richmond courtroom were
scandalous to excess. It was understood that Chase had instructed the
marshal ‘not to put any of those creatures called Democrats on the jury,’ and
his boasts concerning Virginia lawyers had preceded him. The most brazen
tyranny presided in the case of Callender, and the lawlessness of the Judge
was more threatening than the licentiousness of the culprit. It was a political
inquisition, not a trial. The courtroom was thronged. The case was the sole
topic of conversation in the streets and taverns. The Democrats had no
misapprehensions of the nature of the trial, and three extraordinarily able
lawyers were there for the defense—John Hay, who was afterwards to
prosecute Burr, Nicholas, and William Wirt, already well advanced toward
that professional eminence which he so long enjoyed. There was a dignity
and courage in the aspect of these three men that Chase could only interpret
as a challenge. He had made his boasts. He would teach these Virginia
lawyers—and there was nothing apologetic or fawning in the manner of Hay,
Nicholas, or Wirt. The fact that neither was there anything of insolence made
matters worse. Feeling himself on the defensive, Chase sought to conceal his
embarrassment in the brutality of his conduct.
The shameful story of that travesty of a trial has been often told, and it
played a part in the impeachment proceedings against Chase a little later. He
stormed, fumed, spluttered, and injected Federalist stump speeches into the
ludicrous proceedings. He refused the defense permission to ask a
prospective juror if he had formed and expressed an opinion on the
Callender pamphlet. ‘The question is improper and you shall not ask it,’ he
thundered. When John Taylor of Caroline was put on the witness stand,
Chase nervously demanded what the defense intended to prove by the
witness. He was told. ‘Put the question in writing and submit it to me,’ he
demanded. But why, asked Nicholas, when nothing of the sort is required in
questioning witnesses for the prosecution? ‘It’s the proper procedure,’ fumed
the Court. Keeping a firm rein on both his temper and his contempt for the
Court, Nicholas submitted three questions in writing. One glance, and Chase
ruled them out. The Virginia lawyers showed their amazement. Even Chase
could see it. ‘My country has made me a Judge,’ he shouted, ‘and you must
be governed now by my opinion.’
William Wirt rose to submit an argument on the admissibility of the
evidence. He began with observations on the embarrassments of the defense
because Callender had been ‘presented, indicted, arrested, and tried during
this term and had not been able to procure testimony essential to a proper
defense.’ He even hinted at the precipitancy of the Court.
‘You must not reflect on the Court,’ shouted Chase.
‘I am prevented from explaining to you [the jury] the causes which have
conspired to weaken our defense, and it is no doubt right that I should be
prevented, as the Court has so decided.’
Chase saw at once that he was not going to care much for this ‘young
man,’ as he contemptuously called him repeatedly. Wirt proceeded to an
attack on the constitutionality of the Sedition Law.
‘Take your seat, sir,’ stormed the livid-faced Chase. ‘Ever since I came
into Virginia I have understood that sort of thing would be urged, and I have
deliberated on it.’ Whereupon he produced a long manuscript and prepared
to read. ‘Hear my words,’ he admonished, glaring around the courtroom. ‘I
wish the world to know them—my opinion is the result of mature
reflection.’
Wirt undertook to argue the point—Chase gesticulated, stormed, insulted
—and William Wirt folded his papers, and resuming his seat declined to
continue. Hay took up the argument, to be met constantly with barking
interruptions, until he, too, in sheer disgust, folded his papers and sat down.
‘Please to proceed,’ urged Chase, wondering perhaps if he had gone too
far with these Virginia lawyers, ‘and be assured that you will not be
interrupted by me, say what you will.’ Hay refused to continue the farce.
Thus, throughout, the mobbing of Callender and his attorneys went on.
The result was conviction and a jail sentence.[1557]

Meanwhile, a serio-comedy in New York State which was working

effectively for the Democrats. In the early spring of 1800, John Armstrong,
author of the ‘Newburgh Letters,’ and until this time an ardent Federalist,
outraged by the brazen attempt to suppress free speech and the freedom of
the press, prepared a powerful and vituperative petition for the repeal of the
Sedition Law and sent it into several counties to be circulated for signatures.
In Otsego, then a new and undeveloped part of the State, it was entrusted to
Jedekiah Peck, an eccentric character known to every man, woman, and
child in the county. Poor to poverty, he had combined the work of an
itinerant surveyor with that of a preacher, and was popular as both.
Wandering through the country surveying land by day, night found him in
some settler’s home preaching and praying, and, in the intervals between, he
talked politics. He had baptized the infant, preached the funeral sermons for
the dead, married the young, prayed for and with the old. His sincerity was
apparent, his innate kindliness manifest. Many smiled at the diminutive old
man, but most men and all children loved him. Burr, who had a genius for
using the right man in the right place, took him up and had him sent to the
Legislature as a Federalist.[1558]
Right joyously the little old man started on his rounds with the petition.
When his activity was made known to Judge William Cooper, father of the
novelist, and temperamentally as unfit for the Bench as a large number of the
Judges of the time, he boiled with rage. Instantly he wrote the District
Attorney of Peck’s heinous sedition. Immediately a grand jury was
empaneled in the city of New York. A bench warrant for Peck’s arrest was
issued. At midnight he was dragged from his bed, placed in manacles like a
dangerous criminal, and the two-hundred-mile march to New York began.
The roads were bad, progress was slow, the news spread, and in every
village and at every crossroads crowds poured forth to look upon the pitiful
spectacle and to sympathize with the victim. Jefferson could not have
planned a more effective campaign tour. The plain people of the countryside
knew Peck—and they turned away with a sense of personal outrage. For five
days the march continued—it was a triumphant march for democracy.
Thus the uneducated, itinerant preacher and surveyor of Otsego County
made his contribution to the election of Jefferson, marching in manacles to
illustrate the Federalist conception of liberty.[1559]
Merrily the Terror sped along.

XI

The New London ‘Bee,’ under the editorship of Charles Holt, a

Jeffersonian, had greatly annoyed the Federalists of the surrounding States,
and a remedy was now at hand. Had it not attacked the French war—and
therefore tried to prevent enlistments? Here was sedition. The editor was
arrested, his own brother summoned as a witness against him. There was
more than one War of the Roses in those days. The paper on which he was
indicted was furnished by two Federalist editors, one of whom had two
brothers on the jury that brought in the indictment. The foreman of the grand
jury was an Amos Bull who had been a British commissary in New York
during the Revolution.[1560] Bushrod Washington presided at the trial. The
defense undertook to show the Sedition Law unconstitutional and the
charges of the ‘Bee’ true. The friends of Holt ‘had collected from Dan to
Beersheba to hear the trial and afford aid and comfort to their brother.’ When
he was quickly convicted and sentenced to jail for three months and to pay a
fine of two hundred dollars, a Federalist paper smugly commented upon the
‘mildness of the punishment’ and ‘the humanity of the Judges.’[1561] Like
the other victims of the Terror, Holt took his punishment standing up, with
shoulders thrown back. A few days before his trial he wrote boldly of the
things he had refrained from saying—‘the insults and threats offered to
peaceable inhabitants and helpless women in the neighborhood, and the
alarm and disturbance excited by firing in the streets and under the windows
at all hours of the night.’[1562]
During the two years of the Terror the press was sprinkled with brief
reports on arrests, mostly of Democratic editors. One at Mount Pleasant,
New York, was arrested ‘in the name of the President for reprinting a
paragraph from the New Windsor Gazette supposed to be a libel against the
President,’ and he was forced to give bond for four thousand dollars.[1563]
By November, 1798, it was announced that twenty-one ‘printers’ had ‘fallen
victims to the ... Sedition Law.’[1564] In enumerating the arrests that month,
the ‘Chronicle’ commented that no Federalist editor was included ‘because
they vilify none but Jefferson, Livingston, and Gallatin.’[1565] Everywhere
men were being intimidated into silence. Sometimes there was a touch of
comedy to the Terror. One poor wight was dragged into court because of a
comment, when a salute was fired in honor of Adams, that it was a pity the
ball did not find lodgment ‘in the seat of his pants.’
Strangely enough, there was no serious attempt to make use of the Alien
Law. We have seen that about the time of its passage many Frenchmen
chartered a boat to escape its operations, and America thus rid herself of the
peril of Volney. General Victor Collot, an officer in the army of
Rochambeau, escaped deportation by leaving voluntarily. The only appeal to
the Alien Law was by indirection in the case of John D. Burk, editor of the
‘Time Piece,’ a democratic paper in New York City. He had left his native
Ireland to escape the terror there under Pitt, and finally ran foul of the law
here by charging that a letter of Gerry to Adams, which the latter had sent to
Congress, had been tampered with. The terrorists were not slow to act. When
the offensive article stared at Pickering through his spectacles, he wrote the
District Attorney: ‘If Burk is an alien no man is a fitter object for the
operation of the Alien Law. Even if Burk should prove to be an alien it may
be expedient to punish him for his libels before he is sent away.’ He had
already been arrested for sedition, however, and the prosecution was finally
dropped on condition that he would leave the country. Instead of leaving, he
went into hiding, only emerging from his obscurity with the inauguration of
Jefferson.[1566]
Many of the terrorists were infuriated by the failure to use the Alien Law
for wholesale deportations. ‘Why in God’s name is the Alien Law not
enforced?’ wrote the intolerant Tracy to McHenry.[1567] Everywhere the
Sedition Law was keeping men ‘on the run.’ E. S. Thomas, learning that
Thomas Adams, of the ‘Independent Chronicle,’ had been arrested for the
publication of an article by the former, fled to South Carolina just in time.
[1568] In the capital at Philadelphia, the Jeffersonians, fearing an attack, met
in secret and made plans for defense. Moreau De Saint Merys, a scholarly
Frenchman who kept a bookstore, was given keys to two houses where he
could take refuge should his own be attacked. He was quite incapable of
anything that would have made him amenable to the law, and President
Adams had not only lounged in his bookstore frequently, but the two had
exchanged copies of their books. Hearing that Adams had written him down
among the proscribed, Moreau appealed to Senator Langdon for the reason.
‘No reason,’ grunted Langdon, ‘beyond the fact that you are French.’
Finally, thanks to the courtesy of Liston, the British Minister, Moreau
secured a passport and left the land of liberty with his books, maps, and
papers.[1569]
Drunk with hate and a sense of power, the terrorists were running amuck.
At a banquet at Hartford in July, 1799, they thrilled to the toast: ‘The Alien
and Sedition Laws: Like the Sword of Eden may they point everywhere to
guard our country against intrigue from without and faction from
within.’[1570] And every Democrat knew that ‘faction’ was the Federalist
name for party, and ‘party’ meant the Jeffersonians. Armed with the sword,
the Federalists no longer bandied idle words. When George Nicholas of
Kentucky challenged Robert Goodhue Harper to a debate through the press
on the Sedition Law, the latter was merely amused. ‘The old proverb says,
let them laugh who win; and for the converse of the maxim the consolation
of railing ought to be allowed to those who lose,’ jeered Harper.[1571] Why
argue? The courts were busy silencing and jailing the Jeffersonians,
suppressing free speech, striking down the liberty of the press.
 With the Democrats partly intimidated in the Eastern States, the honor of
leading the fight against these laws was reserved for Virginia and the frontier
States of Kentucky and Tennessee. Here mass meetings were held
throughout the autumn of 1798. In Woodford County, Kentucky, it was
declared ‘the primary duty of every good citizen to guard as a faithful
sentinel his constitutional rights and to repel all violations of them from
whatever quarter offered.’[1572] Four hundred gathered in Goochland
County, Virginia, and, with only thirty opposed, denounced the laws and
called upon the next Assembly to protest to Congress.[1573] At
Charlottesville, at the foot of Monticello, the people of Albemarle County,
Virginia, met to adopt resolutions of denunciation, and at Lexington,
Kentucky, they added their protest.[1574] Richmond—Knoxville—followed.
These resolutions were dignified and forceful protests, sponsored by men of
the first ability in the communities acting. But in the House of
Representatives at Philadelphia, when Jeffersonians spoke in favor of the
repeal of the obnoxious measures, their voices were drowned by loud
conversation, coughs, laughter, the scraping of the feet of the Federalists.
‘Livingston, however, attempted to speak,’ wrote Jefferson, ‘but after a few
sentences the Speaker called him to order.... It was impossible to
proceed.’[1575] From 1798 until 1801, liberty was mobbed in America with
the zealous support of the Federal Courts, to the applause of the church—
and out of these conditions came the Virginia and Kentucky Resolutions.

XII

On the adjournment of Congress in 1798, Jefferson returned to his

Virginia home profoundly impressed with the significance of the obnoxious
laws. He had supposed that the freedom of speech and the liberty of the
press had been guaranteed by the Constitution. That the fundamental law
was outraged by these measures he had no doubt. It was his firm conviction
that they had been enacted ‘as an experiment on the American mind to see
how far it will bear an avowed violation of the Constitution,’ and that if it
succeeded ‘we shall immediately see attempted another act of Congress
declaring that the President shall continue in office for life.’[1576] He was
not alone in this belief.
One day in the late summer a memorable conference was held at
Monticello. There, in the center of the group, was Jefferson. There, too, was