Translational Autoimmunity, Volume 1 :

Etiology of Autoimmune Diseases Nima

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 Translational Immunology
TRANSLATIONAL AUTOIMMUNITY,
VOL. 1
This page intentionally left blank
 Translational Immunology
TRANSLATIONAL
AUTOIMMUNITY,
VOL. 1
Etiology of Autoimmune Diseases

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
Academic Press
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 Dedication

This book would not have been possible without continuous encouragement by my family.
I wish to dedicate it 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 4 Conclusion 40
Preface xv References 41

Series editor biography xvii 4. T cell recognition of neoepitopes

Acknowledgment xix in autoimmunity
Abbreviations xxi Eddie A James

1 Introduction 47
1. Introduction on translational 2 The mystery of lost tolerance in
autoimmunity 49
autoimmunity: From bench to bedside 3 Determinant spreading in autoimmune disease 49
Nima Rezaei and Niloufar Yazdanpanah 4 Neoepitopes as a challenge to immune tolerance 51
5 T cell recognition of citrullinated neoepitopes in
1 Introduction 1
rheumatoid arthritis 53
2 Autoimmune disorders 2
6 T cell recognition of deamidated neoepitopes in
3 Pathogenesis and mechanisms of autoimmune
CD 53
diseases 3
7 T cell recognition of neo-antigens in T1D 53
4 Predisposing factors 4
8 Prospects for diagnostic detection of neoepitope
5 Role of genetics 5
specific T cell responses 55
6 Obstacles in treatment 6
9 Conclusion 56
7 Diagnostic tools 7
References 56
8 Role of innate immunity 8
9 Conclusion 8
References 9 5. Role of Th1 and Th2 in autoimmunity
Giacomo Ramponi, Enrico Brunetta, and Marco Folci

2. Autophagy in autoimmunity
1 Introduction 62
Ting Gan and Xu-jie Zhou
2 Th1 and Th2 generation 65
3 Th1 and Th2 response in health 69
1 Introduction 13
4 Breakdown of tolerance: Autoimmunity and
2 An overview of autophagy 14
allergy 75
3 Autophagy in immunity 15
5 Conclusion 79
4 Autophagy in autoimmune diseases 20
References 80
5 Conclusion 25
References 26
6. Role of Th17 cell in tissue inflammation
3. Immunometabolism and autoimmunity and organ-specific autoimmunity
Valentina Pucino Rajdeep Dalal, Srikanth Sadhu, and Amit Awasthi

1 Introduction 31 1 Introduction 94
2 Immunometabolism in homeostasis 32 2 Differentiation of IL-17-producing Th17 cells 95
3 Immunometabolism in autoimmunity 36 3 Amplification of Th17 cells 97
4 Stabilization of Th17 cells 98

vii
viii Contents

5 Transcriptional regulation of Th17 cells 99 10. The role of type III interferons
6 Regulators of Th17 cells 102 in systemic autoimmune
7 Small molecules inhibitor of Th17 cells 104
diseases
8 Role of Th17 cells in the pathogenesis of
Mauricio Mora-Ramírez and Luis M. Amezcua-Guerra
autoimmune diseases 105
9 Conclusion 111
1 Introduction 199
References 115
2 The type III interferon family 200
3 Production of type III interferons 200
7. Peptide editing and its modulation 4 Response of target cells to type III
in CD4+ T cell tolerance to self interferons 201
Miguel Álvaro-Benito 5 Potential association between interferons and
autoimmunity 203
1 Introduction 124 6 Type III interferons in systemic lupus
2 Cellular adaptive immunity in health and erythematosus 204
disease 124 7 Type III interferons in Sjögren syndrome 206
3 Tolerance mechanisms: training lymphocytes 8 Type III interferons in rheumatoid arthritis 207
for a proper self and non-self 9 Type III interferons in antiphospholipid
recognition 130 syndrome 208
4 Peptide editing in the targets of organ-specific 10 Type III interferons in systemic sclerosis 208
autoimmune diseases 136 11 Conclusion 209
5 Conclusion 137 References 209
References 138
11. Regulation of immunological
8. Innate lymphoid cells in autoimmune
tolerance and human autoimmunity
diseases
by NF-κB
Vijay Kumar
Matthew C. Cook
1 Introduction 144
1 Introduction 214
2 ILCs as crucial components of the mammalian
2 Immunological tolerance 220
immune system 147
3 Monogenic NF-κB defects and human
3 ILCs in ADs 155
autoimmunity 223
4 Conclusion 163
4 Conclusion 227
References 164
References 230
9. Autoimmune diseases and the role
of Toll-like receptor-7 and -9 signaling 12. Micro RNA, circular RNA,
cascades neutrophils, and myeloperoxydases
Emma J. Keller, Neeva B. Patel, and Trine N. Jorgensen
in autoimmune diseases
Melek Kechida and Syrine Daadaa
1 Introduction 177
2 Toll-like receptors 178 1 Introduction 235
3 Autoimmune disorders with a role for TLR7 or 2 Micro ribonucleic acids (MicroRNAs) 236
TLR9 180 3 Circular RNAs 238
4 Manipulation of TLR7 and TLR9-induced 4 Neutrophils 241
signaling 186 5 Myeloperoxidase in autoimmune diseases 245
5 Conclusion 190 6 Conclusion 247
References 190 References 247

13. Human leukocyte antigen and
autoimmunity
Sally Elfishawi and Mohanad Elfishawi
1 Introduction 255
2 HLA genetic organization and protein
structure 256
3 Autoimmune HLA disease association 257
4 Mechanisms involved in HLA-mediated
autoimmune pathology 258
5. Conclusion 262
References 262
14. HLA-G-mediated immunological
tolerance and autoimmunity
Hui-Hui Xu, Aifen Lin, and Wei-Hua Yan
1 Introduction 266
2 Genetic variation of HLA-G gene 266
3 Molecular structure of HLA-G 268
4 HLA-G expression regulation 269
5 HLA-G and receptor signaling pathways 271
6 HLA-G and autoimmunity 274
7 Implication of HLA-G-mediated immune
tolerance in autoimmunity 280
8 Conclusion 282
References 282
15. The immune system and the
microbiota: The two sides of mucosal
tolerance
Claudio Costantini
1 Introduction 297
2 Microbiota 298
3 Mucosal immune system 300
4 Mucosal tolerance 300
5 Mechanisms of mucosal tolerance toward
commensal bacteria 301
6 Tolerance breaking at the mucous membranes
and autoimmune diseases 309
7 Conclusion 310
References 311
ix
Contents  
16. Role of free radicals in autoimmune
diseases
Haseeb Ahsan, Mohammad Yusuf Hasan, and Rizwan Ahmad
1 Introduction 318
2 Pathophysiology of free radicals 319
3 Inflammation and autoimmune diseases 319
4 Rheumatoid arthritis 320
5 Systemic lupus erythematosus 321
6 Conclusion 323
References 323
17. Immunological tolerance and
autoimmunity
Adrian Zelada Valdes
1 Introduction 326
2 Central tolerance of T cells and autoimmunity 326
3 Peripheral T cell tolerance and autoimmunity 335
4 Central B cell tolerance and autoimmunity 339
5 Peripheral B cell tolerance and autoimmunity 340
6 Conclusion 340
References 341
18. Construction of bioscore for detection
of self-tolerance failure: From analysis of
silicosis cases
Suni Lee, Shoko Yamamoto, Yurika Shimizu, Bandaru Srinivas,
Nagisa Sada, Naoko Kumagai-Takei, Tatsuo Ito, Yasumitsu
Nishimura, Masayasu Kusaka, Kozo Urakami, and Takemi Otsuki
1 Introduction 348
2 Effects of silica particles on human
immune cells 350
3 Generating a bioscore/autoimmune score to detect
early dysregulation of autoimmunity 352
4 Conclusion 354
References 354
Index 357
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 Contributors

Rizwan Ahmad College of Medicine, Imam Institute, NCR-Biotech, Science Cluster, Farid-
Abdulrahman bin Faisal University, Dammam, abad, Haryana, India
Saudi Arabia Mohanad Elfishawi Division of Rheumatology,
Haseeb Ahsan Faculty of Dentistry, Depart- Department of Medicine, Mayo Clinic, Roches-
ment of Biochemistry, Jamia Millia Islamia, ter, MN, United States
New Delhi, India Sally Elfishawi BMT lab unit, Clinical Pathol-
Miguel Álvaro-Benito Laboratory of Protein Bio- ogy Department, National Cancer Institute,
chemistry, Institute for Chemistry and Biochemis- Cairo University, Cairo, Egypt
try Department of Biology, Chemistry, Pharmacy,
Marco Folci Humanitas Clinical and Research
Free University Berlin, Berlin, Germany Center – IRCCS, via Manzoni 56, Rozzano;
Luis M. Amezcua-Guerra Health Care Depart- Department of Biomedical Sciences, Humani-
ment, Universidad Autónoma Metropolitana-­ tas University, Pieve Emanuele; Network of
Xochimilco; Department of Immunology, Immunity in Infection, Malignancy and Auto-
Instituto Nacional de Cardiología Ignacio immunity (NIIMA), Universal Scientific Educa-
Chávez, Mexico City, Mexico tion and Research Network (USERN), MI, Italy
Amit Awasthi Immunobiology Laboratory, Ting Gan Renal Division, Peking University
Translational Health Science and Technology First Hospital; Peking University Institute of
Institute, NCR-Biotech, Science Cluster, Farid- Nephrology; Key Laboratory of Renal Disease,
abad, Haryana, India Ministry of Health of China; Key Laboratory of
Enrico Brunetta Humanitas Clinical and Chronic Kidney Disease Prevention and Treat-
Research Center – IRCCS, via Manzoni 56, ment (Peking University), Ministry of Educa-
Rozzano; Department of Biomedical Sciences, tion, Beijing, People’s Republic of China
Humanitas University, Pieve Emanuele, MI, Mohammad Yusuf Hasan School of Biomedi-
Italy cal Sciences, Newcastle University, Newcastle
Matthew C. Cook Centre for Personalised upon Tyne, United Kingdom
Immunology, John Curtin School of Medical Tatsuo Ito Department of Hygiene, Kawasaki
Research, Australian National University; Medical School, Okayama, Japan
Department of Immunology, Canberra Hospi- Eddie A James Translational Research Program,
tal, Canberra, ACT, Australia Benaroya Research Institute at Virginia Mason,
Claudio Costantini Department of Medicine Seattle, WA, United States
and Surgery, University of Perugia, Perugia, Trine N. Jorgensen Department of Inflamma-
Italy tion & Immunity, Lerner Research Institute,
Syrine Daadaa Internal Medicine and Endo- Cleveland Clinic, Cleveland, OH, United States
crinology Department, Fattouma Bourguiba Melek Kechida Internal Medicine and Endo-
University Hospital, University of Monastir, crinology Department, Fattouma Bourguiba
Monastir, Tunisia University Hospital, University of Monastir,
Rajdeep Dalal Immunobiology Laboratory, Monastir, Tunisia
Translational Health Science and Technology

xi
xii Contributors
Emma J. Keller Department of Inflammation &
Immunity, Lerner Research Institute, Cleveland
Clinic, Cleveland, OH, United States
Naoko Kumagai-Takei Department of Hygiene,
Kawasaki Medical School, Okayama, Japan
Vijay Kumar Department of Pharmaceutical
Sciences, College of Pharmacy, University of
Tennessee Health Science Center, Memphis,
TN, United States
Masayasu Kusaka Kusaka Hospital, Okayama,
Japan
Suni Lee Department of Hygiene, Kawasaki
Medical School, Okayama, Japan
Aifen Lin Biological Resource Center, Taizhou
Hospital of Zhejiang Province, Wenzhou
Medical University; Key Laboratory of Mini-
mally Invasive Techniques & Rapid Rehabili-
tation of Digestive System Tumor of Zhejiang
Province, Taizhou Hospital of Zhejiang Prov-
ince, Linhai, Zhejiang, China
Mauricio Mora-Ramírez Department of
Internal Medicine, General Hospital No.
8 Gilberto Flores Izquierdo, IMSS; Health
Care Department, Universidad Autónoma
­Metropolitana-Xochimilco, Mexico City, Mexico
Yasumitsu Nishimura Department of Hygiene,
Kawasaki Medical School, Okayama, Japan
Takemi Otsuki Department of Hygiene, Kawa-
saki Medical School, Okayama, Japan
Neeva B. Patel Department of Inflammation &
Immunity, Lerner Research Institute, Cleveland
Clinic, Cleveland, OH, United States
Valentina Pucino Institute of Inflammation
and Ageing, College of Medical and Dental
Sciences, University of Birmingham; Hospitals
Birmingham NHS Foundation Trust, Queen
Elizabeth Hospital, Queen Elizabeth Medical
Centre, Birmingham, United Kingdom
Giacomo Ramponi Humanitas Clinical and
Research Center – IRCCS, via Manzoni 56,
Rozzano, MI, Italy
Nima Rezaei Research Center for Immunode-
ficiencies, Children’s Medical Center; Depart-
ment of Immunology, 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
Nagisa Sada Department of Biophysical Chem-
istry, Graduate School of Medicine, Dentistry
and Pharmaceutical Sciences, Okayama Uni-
versity, Okayama, Japan
Srikanth Sadhu Immunobiology Laboratory,
Translational Health Science and Technology
Institute, NCR-Biotech, Science Cluster, Farid-
abad, Haryana, India
Yurika Shimizu Department of
­Pathophysiology-Periodontal Science,
Okayama University Graduate School of Med-
icine, Dentistry and Pharmaceutical Sciences,
Okayama, Japan
Bandaru Srinivas Department of Hygiene,
Kawasaki Medical School, Okayama, Japan
Kozo Urakami Hinase Urakami Iin, Okayama,
Japan
Adrian Zelada Valdes Immunology Depart-
ment, Institute of Basic and Preclinical Sci-
ences “Victoria de Girón”; Department of Basic
Sciences, Faculty of Medical Sciences; Allergy
Department and Havana Hematology Service,
General Teaching Hospital “Dr. Enrique
Cabrera”, University of Medical Sciences of
Havana, Havana, Cuba
Hui-Hui Xu Medical Research Center, Taizhou
Hospital of Zhejiang Province, Wenzhou
Medical University; Key Laboratory of Mini-
mally Invasive Techniques & Rapid Rehabili-
tation of Digestive System Tumor of Zhejiang
Province, Taizhou Hospital of Zhejiang Prov-
ince, Linhai, Zhejiang, China
Shoko Yamamoto Department of Hygiene,
Kawasaki Medical School, Okayama, Japan
Wei-Hua Yan Medical Research Center, Taizhou
Hospital of Zhejiang Province, Wenzhou
Medical University; Key Laboratory of Mini-
mally Invasive Techniques & Rapid Rehabili-
tation of Digestive System Tumor of Zhejiang
Province, Taizhou Hospital of Zhejiang Prov-
ince, Linhai, Zhejiang, China
 Contributors xiii
Niloufar Yazdanpanah Research Center for Xu-jie Zhou Renal Division, Peking University
Immunodeficiencies, Children’s Medical First Hospital; Peking University Institute of
Center, Tehran University of Medical Sciences; ­Nephrology; Key Laboratory of Renal Disease,
Network of Immunity in Infection, Malig- Ministry of Health of China; Key Laboratory of
nancy and Autoimmunity (NIIMA), Universal Chronic Kidney Disease Prevention and Treat-
Scientific Education and Research Network ment (Peking University), Ministry of Educa-
(USERN), Tehran, Iran tion, Beijing, People’s Republic of China
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 Preface
The scientific world has witnessed many
remarkable developments in the field of
immunology during recent decades. The
novel discovery of genes related to different
immune-mediated diseases has enhanced
­ Autoimmune Diseases, is a comprehensive
our knowledge about the immune system
and its interactions with other systems in the
human body and enlightened different as-
pects of its complexity that lead to promote
diagnostic strategies, design more efficient
therapeutic agents, and reduce the potential
morbidities and mortality. Due to the broad
spectrum of immune-mediated diseases,
from immunodeficiency to hypersensitivity
and autoimmune diseases, the immune sys-
tem diseases collectively contribute to a con-
siderable prevalence, although every single
immune-mediated disease represents a low
prevalence.
The concern of applying the latest re-
search findings has long been with scien-
tists. Translational research is recognized
as a potential tool to utilize scientific find-
ings in clinical settings and patients’ care.
Considering the wide spectrum of diseases
xv
related to the immune system besides the
huge burden of them for individuals, health
care settings, families, and society, identi-
fying promising alternative diagnostic and
therapeutic strategies through translational
studies is of interest.
Translational Immunology Book Series is a
major new suite of books in immunology,
which cover both basic and clinical immunol-
ogy. The series seeks to discuss and provide
foundational content from bench to bedside
in immunology. This series is intended to
discuss recent immunological findings and
translate them into clinical practice. The first
volumes of this book series are specifically
devoted to autoimmune diseases.
Translational Autoimmunity: Etiology of
book covers underlying mechanisms that
contribute to the occurrence of autoimmu-
nity. Volume 1 has pictured an overview of
intrinsic pathways that provoke and initiate
the autoimmune process besides providing
comprehensive information regarding the
endogenous and exogenous predisposing
factors that contribute to the emergence of
autoimmune diseases. To fully picture these
factors and pathways in connection with to-
gether, Chapter 1 provides an introduction
to the whole of this system and introduces its
different components and their interconnec-
tions. Autophagy, as a fundamental mech-
anism in immune responses, is explored
in autoimmune conditions in Chapter 2.
Concerning the growing attention to the re-
programming process of immune cells by al-
teration in their metabolic states, Chapter 3
is devoted to the ­ immunometabolism in
xvi Preface
a­utoimmunity. Since the contribution of
both adaptive and innate immune systems
to the induction of autoimmunity have
been widely discussed, different chapters
are designed regarding the role of adaptive
immunity (Chapter 4 on the recognition of
neoepitopes, Chapter 5 on the role of Th1
and Th2 cells, Chapter 6 specifically about
the effect of Th17 cells, and Chapter 7) and
the innate immunity (Chapter 8 on the in-
nate lymphoid cells and Chapter 9 on the
Toll-like receptors, since they might be
the most involved known components of the
innate immune system involved in autoim-
munity). Moreover, the association of other
important components of the immune sys-
tem with autoimmunity is explained in
Chapter 10 that goes into details about the
role of type III interferons, Chapter 11 that
takes a focused view on the contribution of
NF-kB in immune tolerance, and Chapter 12
explains the association of neutrophils with
other components in autoimmunity. The
content is followed by the effect of human
leukocyte antigen (HLA) in autoimmunity
(Chapters 13 and 14). Different existing
f­actors in the human body are introduced
to have an association with the breakdown
of immune tolerance and consequently, in-
duction of autoimmunity, which microbiota
(Chapter 15) and free radicals (Chapter 16)
are of the mentioned factors. Finally, the
book contains three chapters concerning the
immune tolerance processes to highlight its
significance in the etiopathology of autoim-
mune diseases (Chapters 17 and 18).
The Translational Immunology Book
Series is the outcome of the invaluable con-
tribution of scientists and clinicians from
well-known universities/institutes world-
wide. I would like to hereby appreciate and
acknowledge the expertise of all contributors
for generously devoting their time and con-
siderable effort in preparing their respective
chapters. I would also like to express my
gratitude to Elsevier publication for provid-
ing me the opportunity to publish this book.
Finally, I hope this translational book will be
comprehensible, cogent, and of special value
for researchers and clinicians who wish to
extend their knowledge on immunology.
Nima Rezaei
 Series editor biography
Professor Nima Rezaei obtained his med-
ical degree (MD) from Tehran University of
Medical Sciences and subsequently obtained
an MSc in molecular and genetic medicine
and a PhD in clinical immunology and hu-
man genetics from the University of Sheffield,
United Kingdom. He also spent a short-term
xvii
fellowship of Pediatric Clinical Immunology
and Bone Marrow Transplantation in the
Newcastle General Hospital. Rezaei is now
the 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). Prof. Rezaei has already been
the Director of more than 50 research proj-
ects and has designed and participated in
several international collaborative projects.
Prof. Rezaei is an editorial assistant or board
member for more than 30 international jour-
nals. He has edited more than 30 interna-
tional books, has presented more than 500
lectures/posters in congresses/meetings,
and has published more than 1000 scientific
papers in international journals.
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 Acknowledgment

I would like to express my gratitude to the Editorial Assistant of this book,

Ms. Niloufar Yazdanpanah. With no doubt, the book would not have been completed with-
out her contribution.
Nima Rezaei

xix
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 Abbreviations

AARDA American Autoimmune Related ATG autophagy related gene

Diseases Association ATP adenosine triphosphate
AAV ANCA-associated vasculitides Auto-Abs auto-antibodies
ACC acetyl-CoA carboxylases BAFF B cell-activating factor
ACPA anticitrullinated peptide BALF bronchoalveolar lavage fluid
antibodies BCL B cell lymphoma
AD atopic dermatitis Bcl11b B-cell CLL/lymphoma 11b
AD autoimmune diseases BCRs B cell receptors
ADAP adhesion- and degranulation BENTA B cell expansion with T cell
promoting adaptor protein anergy
ADCC Ab-dependent cell cytotoxicity BLIMP B lymphocyte-induced maturation
AEDID anhidrotic ectodermal dysplasia protein
with immune deficiency BM bone morrow
Ag antigen BMAL1 brain and muscle ARNT-like 1
AhR aryl hydrocarbon receptor Breg B regulatory cell
AICD activation-induced cell death c-ANCA cytoplasmic ANCA
AIDs autoinflammatory diseases CANDLE chronic atypical neutrophilic
AIH autoimmune hepatitis dermatosis syndrome and
AIRDs autoimmune rheumatic diseases elevated temperature
AIRE autoimmune regulator CAPS cryopyrin-associated periodic
AKT Ak strain transforming syndrome
ALPS autoimmune lymphoproliferative CARD caspase recruitment domain-
syndrome containing protein
AMP antimicrobial peptide Carma1 CARD-containing MAGUK
AMPK AMP-activated protein kinase protein 1
ANAs antinuclear antibodies CASP8 caspase 8
ANCA antineutrophil cytoplasmic CAT catalase
antibody CBM CARD11-BCL10-MALT1
anti-dsDNA antidouble stranded DNA CBM Carma1-BCL-10-MAP3K7
anti-MCV antimutated citrullinated CCP cyclic citrullinated peptide
vimentin CCR chemokine receptor
APC antigen presenting cell CCR3 C-C chemokine receptor type 3
APECED autoimmune polyendocrinopathy CD cluster of differentiation
with candidiasis and ectodermal CD celiac disease
dystrophy CD Crohn’s disease
APL antiphospholipid antibodies CD74, or Ii invariant chain
APS antiphospholipid syndrome cDCs conventional dendritic cells
APS autoimmune polyglandular CDR complementary determining
syndrome region
APS-1 autoimmune polyglandular c-FLIP cellular FLICE (FADD-like IL-1β-
syndrome type 1 converting enzyme)-inhibitory
Areg amphiregulin protein
ARNTL aryl hydrocarbon receptor nuclear CFSE 5,6-carboxyfluorescein diacetate
translocator-like protein 1 succinimidyl ester
AS ankylosing spondylitis cGAS cyclic GMP-AMP synthase

xxi
xxii Abbreviations

CHDP cationic host defense peptides EAM experimental autoimmune myositis

CIA collagen-induced arthritis EBV Epstein Barr virus
cIAP cellular inhibitor of apoptosis ECAR extracellular acidification rate
protein ecircRNAs exonic circular RNAs
CILPs common innate lymphoid cell EET eosinophil extracellular trap
progenitors EGFR epidermal growth factor receptor
circRNAs circular RNAs EIciRNAs exon-intron circular RNAs
ciRNAs intronic RNAs Eomes eomesodermin
CLIP class II invariant chain derived EOR endoplasmic overload response
peptides ER endoplasmic reticulum
CLPs common lymphoid precursors ERK extracellular signal-regulated
CLPs common lymphoid progenitor kinase
CMA chaperone-mediated autophagy Ets1 ETS proto-oncogene 1
CMV cytomegalovirus EVs extracellular vesicles
cNK cells cytotoxic natural killer cells FADD Fas-associated protein with death
CNS central nervous system domain
ConA concanavalin A FAO fatty acid oxidation
CQ chloroquine FAS fatty acid synthesis
CRC colorectal cancer FcγR Fcγ-receptors
CREB1 cAMP response element binding FcεRI high-affinity IgE receptor
protein 1 FDA US Food and Drug
CRISPR clustered regularly interspaced Administration
short palindromic repeats FLS fibroblast-like synoviocytes
CRTH2 chemoattractant receptor- FOXO1 forkhead box protein O1
homologous molecule expressed FOXP3 Forkhead box p3
on TH2 cells Foxp3+ forkhead box protein 3+
CS complement system FYB Fyn-binding protein
CSF cerebrospinal fluid G6PD glucose-6-phosphate
cTEC cortical thymic epithelial cell dehydrogenase
CTLA4 cytotoxic T-lymphocyte antigen 4 GAD65 glutamic acid decarboxylase
CYLD cytoskeletal-associated protein- GALT gut-associated lymphoid tissue
glycine-conserved domains GC germinal center
DAMPs death/damage-associated G-CSF granulocyte-colony stimulating
molecular patterns factor
DcR3 decoy receptor 3 Gfi1 growth factor independent 1
DCs dendritic cells transcription factor
DMARDs disease modifying antirheumatic GLUT glucose transporter
drugs GM-CSF granulocyte-macrophage colony-
DMF dimethyl-fumarate stimulating factor
DMTs disease modifying therapies GoF gain-of-function
DN double negative GPI glycosylphosphatidylinositol
DNA-IC DNA-containing immune GPx glutathione peroxidase
complexes GrA or GrB granzyme A or granzyme B
DNAM-1 DNAX accessory molecule-1 GSH glutathione
DP double positive GSSG glutathione disulfide
DQ2 HLA-DQB1*02:01 GWAS genome-wide association study
DQ8 HLA-DQB1*03:02 H2 histocompatibility antigen 2
DR3 death receptor 3 H2O2 hydrogen peroxide
DRiP defective ribosome products HCQ hydroxychloroquine
dsDNA double stranded DNA HCV hepatitis C virus
EAE experimental autoimmune HIF-1α hypoxia-inducible factor-1
encephalomyelitis HIPK3 homeodomain interacting protein
EAH experimental autoimmune kinase 3
hepatitis HIPs hybrid insulin peptides
 Abbreviations xxiii
HK2 hexokinase 2 IRAK interleukin-1 receptor-associated
HLA human leukocyte antigen kinase
HLA-G human leukocyte antigen-G IRAK-1 IL1-receptor-associated-kinase
HMGB1 high mobility group B1 IRF interferon regulatory factor
4-HNE 4-hydroxynonenal IRF7 interferon regulatory factor 7
HOIL heme-oxidized IRP2 ubiquitin ISC interferon signaling compartment
ligase ISG interferon-stimulated gene
HOIP heme-oxidized IRP2 ubiquitin ISRE interferon-stimulated response
ligase-1-interacting protein elements
Hopx homeodomain-only protein ITAM immunoreceptor tyrosine-based
homeobox activation motif
HSCs hematopoietic stem cells ITIMs immunoreceptor tyrosine-based
HSP heat shock protein inhibitory motifs
HSPA8/HSC70 heat shock proteins family A KIR killer-cell immunoglobulin-like
member 8 receptor
HSV-1 herpes simplex virus type 1 KO knock out
HV healthy volunteers KSHV Kaposi’s sarcoma-associated
IA inflammatory arthritis herpesvirus
IA-2 islet antigen-2 LAG-3 lymphocyte activation gene 3
3-IAld indole-3-aldehyde LAMP-2A lysosome-associated membrane
IAPP islet amyloid polypeptide protein type 2A
IBD inflammatory bowel disease LAP LC3-associated phagocytosis
ICA islet cell antibodies LD linkage disequilibrium
Id2 inhibitor of DNA-binding 2 or LDGs low-density granulocytes
inhibitor of differentiation 2 LKB1 liver kinase B1
Id3 inhibitor of DNA-binding 3 or LN lupus nephritis
inhibitor of differentiation 3 LN lymph node
IDO indoleamine-2,3-dioxygenase lncRNA long noncoding RNA
ieILC1s intraepithelial ILC1s LoF loss-of-function
IEL intraepithelial lymphocytes LPS lipopolysaccharide
IFN interferon LTA lipotechoic acid
IFN-α interferon-α LTbR lymphotoxin b receptor
IFN-β interferon-β LTi cells lymphoid tissue inducer cells
IFN-γ interferon-gamma LUBAC linear ubiquitin chain assembly
Ig immunoglobulin complex
IgE immunoglobulin E β2m β2-microglobulin
IgG immunoglobulin G 3-MA 3-methyladenine
IGRP islet-specific glucose-6- MAGUK membrane-associated guanylate
phosphatase catalytic subunit kinase
related protein MAIT mucosal-associated invariant T
IkB inhibitor of NF-kB MALT mucosa-associated lymphoid tissue
IKK inhibitor of NF-kB kinase MALT1 mucosa-associated lymphoid
IL interleukin tissue lymphoma translocation
ILC innate lymphoid cells protein 1
ILC2 type 2 innate lymphoid cells MAMPs microbe-associated molecular
ILFs isolated lymphoid follicles patterns
ILT immunoglobulin-like transcripts MAN1A2 mannosidase alpha class 1A
iNKT invariant natural killer T cell member 2
INS/DEL insertion/deletion MAO monoamine oxidase
IP-10 IFN-γ induced protein 10 MAP3K7 mitogen-activated protein kinase
IPA indole-3-propionic acid kinase kinase 7
IPEX immunodysregulation MAPK mitogen-activated protein kinase
polyendocrinopathy enteropathy, MARCO macrophage receptors with
X-linked collagenous structure
xxiv Abbreviations

MBP myelin basic protein NKT natural killer T cells

MCT monocarboxylate transporters NLR nucleotide-binding
MDA malondialdehyde oligomerization domain (NOD)-
MDSCs myeloid-derived suppressive cells like receptor
MEK mitogen-activated extracellular NLRP3 NLR family, pyrin domain
signal-regulated kinase containing 3 protein
MG myasthenia gravis NNS nonstructural proteins
MHC major histocompatibility complex NO nitric oxide
MHC-I or MHC-II major histocompatibility NOD nonobese diabetic
complex-I or -II NOS nitric oxide synthases
MHP mitochondrial hyperpolarization NOX2 NADPH oxidase-2
MICA MHC class I polypeptide-related Nr1d1 nuclear receptor subfamily 1
sequence A group D member 1
mIgD membrane immunoglobulin D NZB New Zealand black
mIgM membrane immunoglobulin M NZBWF1 (NZB x NZW)F1
MIP-1α macrophage inflammatory NZM New Zealand mixed
protein-1α NZW New Zealand white
miRNA microRNA O2− superoxide anion
MMP-3 matrix metalloproteinase 3 OCR oxygen consumption rate
MOG myelin oligodendrocyte ODN oligodeoxynucleotide
glycoprotein OH hydroxyl radical
MPO myeloperoxidase 8-OHdG 8-hydroxydeoxyguanosine
MRL Murphy Roths Large ONOO− peroxynitrite
mRNAs messenger RNAs OTULIN ovarian tumor domain-containing
MS multiple sclerosis deubiquitinase with linear linkage
mtDNA mitochondrial DNA specificity
mTEC medullary thymic epithelial cell OXPHOS oxidative phosphorylation
mTOR mammalian target of rapamycin PAD peptidylarginine deiminase
mtROS mitochondrial reactive oxygen PADs peptidyl arginine deiminase
species enzymes
MyD myeloid differentiation primary PAMP pathogen-associated molecular
response patterns
NADH nicotinamide adenine p-ANCA perinuclear ANCA
dinucleotide pAPCs professional antigen presenting
NADPH nicotinamide adenine cells
dinucleotide phosphate PBC primary biliary cirrhosis
NALT nasal-associated lymphoid tissues PBMC peripheral blood mononuclear cell
ncHLAII nonclassical human leukocyte PCs plasma cells
antigen PD-1 programmed cell death 1
Ncr1 natural cytotoxicity triggering pDC plasmacytoid dendritic cells
receptor 1 PDK pyruvate dehydrogenase kinase
ncRNAs noncoding RNAs Per3 period homologous 3
NEMO NF-kB essential modulator PFKFB3 6-phosphofructo-2-kinase/
NET neutrophil extracellular trap fructose-2,6-bisphosphatase
NFIL3 nuclear factor IL-3 regulated PGE2 prostaglandin E2
NF-kB nuclear factor kappa-light-chain- PGRPS peptidoglycan recognition protein
enhancer of activated B cells S
NIAID National Institute of Allergy and PI3K phosphoinositide 3-kinase
Infectious Diseases PIR-B inhibitory receptor paired
NIK NF-kB inducing kinase immunoglobulin-like receptor-B
NIMA noninherited maternal antigens PLP proteolipid protein
NKPs natural killer cell precursors PLZF promyelocytic leukemia zinc
NKreg regulatory natural killer cell finger
NKs natural killer cells PMA phorbol myristate acetate
 Abbreviations xxv
PMD piecemeal degranulation SFTSV severe fever with
pMHCII peptide-MHCII thrombocytopenia syndrome
PMN polymorphonuclear cells virus
PPARs peroxisome proliferator-activated SHARPIN Shank-associated Rel homology
receptors domain-interacting protein
PPI PreProInsulin SHM somatic hypermutation
PPP pentose phosphate pathway SHP Src homology 2 domain
PPs Peyer’s patches containing phosphatase 1
PR3 proteinase-3 SIL silicosis
PRE progesterone response element sIL-2R soluble Il-2R
PRR pattern recognition receptor siRNA small-interfering ribonucleotide
PSS Primary Sjogren’s syndrome SIRP-γ signal regulatory protein-γ
PtdSer phosphatidylserine SjS Sjögren’s syndrome
PTM posttranslational modification SLAP-130 SH2-containing leukocyte
PVR poliovirus receptor phosphoprotein of 76 kDa
PXR pregnane X receptor (SLP-76)-associated
R receptor phosphoprotein-130
RA rheumatoid arthritis SLE systemic lupus erythematosus
RA-FLSs rheumatoid arthritis fibroblast- SLEDAI SLE disease activity index
like synoviocytes SLOs secondary lymphoid organs
RAG-1/-2 recombinase activating gene-1/-2 SOD superoxide dismutase
RAGE advanced glycosylation end SP single positive
products-specific receptor SREBPs sterol regulatory element-binding
RANK receptor activator on NF-kB proteins
RANKL receptor activator of nuclear factor SS Sjögren’s syndrome
kappa-Β ligand SSc systemic sclerosis
RANTES regulated on activation normal T ssRNA single-stranded RNA
cells expressed and secreted STAT signal transducer and activator of
RBPs RNA binding proteins transcription
RF rheumatoid factor STAT5 signal transducer and activator of
RHD Rel homology domain transcription 5
RHD rheumatic heart disease STING stimulator of interferon genes
RIG-I retinoic acid-inducible gene I-like T1D type 1 diabetes
receptors T1DM type 1 diabetes mellitus
RIPK receptor-interacting serine/ TAB transforming growth factor-beta-
threonine-protein kinase activated kinase binding protein
RLR RIG-I-like receptor TAK transforming growth factor-beta-
RMST rhabdomyosarcoma 2 associated activated kinase
transcript TAK1 transforming growth factor-β-
RNPs ribonuleoproteins activated kinase 1
RNS reactive nitrogen species TAP transporter associated with
ROR-α receptor-related orphan receptor-α antigen processing
RORγt retinoic-acid-receptor-related T-bet T-box expressed in T cells
orphan nuclear receptor gamma t TCF-1 T cell factor 1
ROS reactive oxygen species TCR T cell receptor
Rroid RNA-demarcated regulatory TECs thymic epithelial cells
region of Id2 TF transcription factor
RSS recombination signal sequences Tfh T follicular helper
s soluble TGF transforming growth factor
SCFA short-chain fatty acid TGF-β transforming growth factor-beta
SCFbTrCP S-phase kinase-associated Th T helper cells
protein1-Cullin1-F-box protein E3 TIGIT T cell immunoglobulin and ITIM
ligase complex domain
sFas soluble Fas TIR Toll/interleukin-1 (IL-1) receptor
xxvi Abbreviations

TLR Toll-like receptor Treg cells T regulatory cells

TNF tumor necrosis factor Treg regulatory T cells
TNFAIP tumor necrosis factor-α induced Tresp responder T
protein TSLP thymic stromal lymphopoietin
TNFR tumor necrosis factor receptor TSSP thymus-specific serine protease
TNFSF11 tumor necrosis factor ligand tTG tissue transglutaminase
superfamily member 11 TTSS type III secretion system
TNF-α tumor necrosis factor-α UC ulcerative colitis
TNTs tunneling nanotubes uORF upstream open reading frames
Tr1 T regulatory type 1 cell UPR unfolded protein response
TRA tissue restricted antigen 5′-URR 5′-upstream regulatory region
TRADD tumor necrosis factor receptor UTR untranslated region
type 1-associated death domain 3′-UTR 3′-untranslated region
protein VEGF vascular endothelial grow factor
TRAF TNF receptor-associated factor VLA-1 very late antigen-1
TRAF tumor-necrosis factor receptor- VNTR variable number of tandem
associated factor repeats
TRAIL TNF-related apoptosis-inducing WHO World Health Organization
ligand wt wild-type
TRANCE TNF-related activation-induced ZnT8 zinc transporter protein 8
cytokine ZO zonula occludens
 C H A P T E R

1
Introduction on translational
autoimmunity: From bench to bedside
⁎
Nima Rezaeia,b,c, and Niloufar Yazdanpanaha,c
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 cNetwork of Immunity in Infection, Malignancy and Autoimmunity
(NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
⁎
Corresponding author

Abstract
The immune system is a potent complex system playing a crucial role in human existence. Immune-based
diseases vary from an inborn defect in the immune system, which results in primary immunodeficiency, to an
overactivation of the immune system, which turns into hypersensitivity states or malfunctions of the immune
system in selfdiscrimination and nonselfdiscrimination, which ends in autoimmune diseases. In this chap-
ter, autoimmune diseases are discussed from different points of view with a translational approach. Recent
advances and discoveries in the field of immunology thoroughly highlight the significance of translational
studies to apply the data from scientific investigations to clinical settings and patient care. Considering the
huge burden of autoimmune diseases on patients, families, health care system, and society, applying trans-
lational research to optimize the current diagnostic tools and therapeutic strategies or to find out promising
alternatives is of interest.

Keywords
Autoimmune disease, Autoimmunity, Immunodeficiency, Immunology, Translational

1 Introduction

Widespread in different tissues, in close contact with various cells, and with meticulous
connections between its different components, the immune system is playing a crucial role in
human survival since the first moment of life. The immune system consists of specific types

Translational Autoimmunity, Vol. 1 1 Copyright © 2022 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/B978-0-12-822564-6.00013-6
 1. Introduction on translational autoimmunity: From bench to bedside

of cells, and each is required to have close, special contact with the body’s various cells and
tissues besides precise correlation with other immune cells to reach the optimal functional
efficacy that is considerably higher than the sum of their individual functions. Cytokines and
chemokines, soluble immune factors, are produced and released by immune cells to conduct
signals and induce the required coordination and synchronicity. Furthermore, to recognize
target cells or tissues, immune cells benefit from a wide variety of receptors, adhesion mol-
ecules, and surface markers. For instance, human leucocyte antigens (HLAs) are a promi-
nent component of this widely extended network that help immune cells with recognition
and discrimination of self and nonself to initiate further responses. The immunology-based
sciences have developed exponentially in the last decades. Recent advances in controlling
hypersensitivity and allergies, fighting against malignancies with the emergence of novel
immunotherapy methods, approval of immune-based drugs and targeted therapies, devel-
opment of genome-wide association studies (GWASs), and discovery ofcontributing genes
to immune-related disorders all have been originated from advances in immunological stud-
ies. Considering recent developments in immunology, different pieces of the immune system
puzzle are assembling and being put together to complete the complex schemaindicating
how various parts of the immune system contribute to preserving human health. Besides
all the aforementioned advances, our understanding of the total architecture of the immune
system has undergone major changes. While the immune components have been categorized
into two main groups, named innate and adaptive immune systems, during recent decades as
our understanding of immune system interactions and interconnections in the human body
increased, the immune system is now introduced as an integration of cross-talks between im-
mune and nonimmune components such as commensal microorganisms [1] and nervous and
endocrine systems [2–4]. Since the number of novel discoveries and developments in the field
of immunology is growing at an unprecedented pace, the concept of “translational immunol-
ogy” has drawn a significant attention, and the importance of bench-to-bedside studies have
been highlighted. Translational research focuses on the application of laboratory findings in
the clinical setting and patient care.
Immune-mediated disorders include a vast spectrum of diseases with different clinical,
histological, pathological, molecular, and laboratory manifestations. Infections, inflammatory
disorders, immunodeficiency conditions, autoimmune disorders, hypersensitivity, and aller-
gies are considered as the main categories of immune-mediated disorders. Moreover, the role
of the immune system in transplant rejection, cancer formation and progression, metabolic
disorders, inflammaging conditions, and neurodegenerative diseases is prominent enough to
restrain the limited categorization and extend the scope of immune-related disorders. The fol-
lowing sections of this chapter is spotlighted on autoimmunity as an immense field of immu-
nology with numerous interconnections and overlaps with other immune-related conditions.

2 Autoimmune disorders

First described with the term “horror autotoxicus” in 1901 by Paul Ehlrich, German bac-
teriologist and immunologist, the scientific world faced a new sophisticated immune-related
condition [5]. Autoimmune diseases are a heterogeneous group of diseases, in which the
immune system lost its tolerance to self-antigens and fails to distinguish between self and

2
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 A PASTORAL.

The little village of my heart

Hath tangled lanes and roses,
And paths of musky hollyhocks
Wherein the wild bee noses.

’Tis summer, summer everywhere,

And drowsy pipes are playing,
Some little peace-dream all the while,
Where sweethearts go a-straying.

Just follow where the piper leads,

With Love—the gypsy rover—
You’ll find the little barefoot joys
You lost out in the clover.

Singlehurst.
 THE WHITE PINE.

’Tis not the grace of yonder beach,

Its crescent-curve and swing,
Nor bastion-crags of Manomet
Whose sarabands I sing.
Mine be those woodland symphonies
Of spirit-power divine,
Like lullabies when evening wraps
The old storm-beaten pine.
Or, be it their defiant chords,
When wintry hordes complain,
While Triton thunders down the gale,
The lightning in his train;
And I would hymn their litanies,
The incense on my breath,
Like Alp-horn notes that echo on
Oblivious of death.

Plymouth,
September 21, 1920.
THE COLONIAL PIONEER.

A soul that like a column white

Survives the wind and rain,
Immortal as the Infinite,
Thy precepts shall remain
While man shall reverence motherhood,
Or galleons sail the seas,
While Earth shall clothe thy mortal frame,
Or leaves shall clothe the trees.
E’en as a shaft of morning burns,
Thy spirit, ever new,
Shall symbol the Eternal mind,
The Brave, the Good, the True.

Knight of the Forum of the Dead,

A hero of the past,
Born of New England’s virgin soil,
Lord of the Nation’s cast
Our daily lot with common men,
Of rectitude of heart,
Give us the burdens of the world
And help us act our part.

And look! some oracle of time—

Some sorcerer of ooze and slime—
Has left a panoply most rare
For lazy-footed night to wear,
With girdle of a sombre dye,
And hung it on a rock to dry,
Where, flushed with slumber, drones a stream
To charm some lonely mermaid’s dream.
And this my heritage, more fair
Than mosque that ever called to prayer
A Moslem, bids me kneel and pray;
These simple words are all I say—
“I’ve been with God an hour or two”—
A shadow tiptoes down the blue;
And like a mother wraps the sea
In stillness of eternity.

Marshfield, August 16, 1920.

THE OLD ROCKIN’ CHAIR.

It tilts a little to the left,

An’ wiggles here and there,
It’s kind-o’ creaky in the j’ints,
An’ ’taint plumb anywhere.

But s’pose you hitch up to’rds the fire,

There, try it ’rond this way;
You’re got to git it joggin’ right,
An’ when you’re tired, w-a-l-l, say,

You’re comforted, you’re comforted,

An’ rested thru an’ thru;
Why, that old rocker’s heaven to me,
But ’taint the same to you.

I ain’t a-goin’ to tell you why,

There ain’t no fairies here,
I h’an’t hearn Annie Laurie sung
For more nor fifty year.

There’s folks what thinks they know “Ben Bolt,”

An’ “Comin’ Thru’ the Rye,”
An’ “Ride away to Boston town,
To make a rabbit pie,”

An’ “Twinkle, twinkle little star,”

But you don’t know ’bout then,
When “Jack the Giant Killer” lived,
An’ Towser ’n’ Uncle Ben.

You don’t know “When they sheared the sheep,”

 An’ “England had a King;”
You never had a trundle-bed;
There, now you’ve got the swing.

Of course it wiggles when you rock,

An’ ’taint plumb anywhere,
But ain’t you full o’ happiness,
In that old rockin’ chair?
OUT OF GETHSAMANE.
Give me the common task,
The little prayers to say,
The common, homely things of life,
To love in the old sweet way.
Give me a wounded heart,
Then bring me the flutes of May,
Teach me ye bells of the summer-grass,
Then give me your tunes to play.
 GREETINGS.
TO THE SOCIETY OF MAYFLOWER DESCENDANTS
IN AMERICA.

A cup to Elder Brewster,

A jewel for his crest,
And every Pilgrim “handed down”
By him and all the rest.
For you, betrothed and plighted,
Forever ships at sea,
Forever world’s to conquer,
And dreams to set you free.

Leagues to the East, forever,

Your spirit outward bound,
Life’s squadrons e’er returning
With treasure yet unfound.
Your soul the soul of Nation,
Your heart the heart of Youth,
Remembering our living dead!
Your sword the sword of Truth.
 LOVE O’ MY HEART.
Give me the same old road,
With its old stone walls and vines,
The same old hearth and the same old friends,
And the same old love that never ends;
Stars in the self-same-sky,
And the long lost dreams of bliss,
In the old-time way,
And my gods of clay,
And the same dear lips to kiss.
Give me the slender hands,
Ah yes, give me the tears,
The same old grief,
And the withered leaf,
The largo of the years.
 TO A FRIEND.
You dread my hand when white and cold,
When death has closed my eyes!
Will mine be then forbidding lips
Because the silence lies
So heavily upon your heart?
Ah, passing sad, ’twere so,
Stay, stay your tears and speak to me,
For I shall surely know,
And at the daybreak I shall come
And touch your face in sleep,
And breathe a thought around your soul,
So tenderly, so deep,
Like unto music it shall be,
Though you no sound shall hear,
Yet in your dreaming you will smile,
And know that I am near.
 “AUNT SALLY.”
Born at Plymouth, June 4th, 1795.

O’ I tell you she’s a picter

That no artist couldn’t draw,
As she sets there in the open kitchen door,
With the sunlight streamin’ down
On her quaint old-fashioned gown,
An’ the shadders stretchin’ in across the floor.

An’ the ivy-vines a-twinin’

Lend a sort o’ glory round,
When the listless autumn lights lie on the land,
There she takes her drowsy nap,
With her Bible in her lap,
Like as ef she’s claspin’ heaven by the hand.

There’s a sort o’ blendin’ beauty

’Twixt her cap-rim an’ her face,
An’ the hollyhocks an’ rustlin’ ripened corn,
An’ the crickets chirpin’ there,
On the soft untroubled air,
“It is harvest time, Aunt Sally, summer’s gone.”
 INTIMACY.

I am part of the greening grass,

A part of the stars and sun.
My heart is a part of the falling dew,
The rose and my soul are one.

I shall live in a silver maple

When the winds and the rain are old;
In the sunset light of a winter night
I shall sail in a ship of gold.

For I am a part of a day gone by,

A part of the years to be,
A part of the strife and the joy of life,
And they each are a part of me.
MY MOTHER’S “BIBLE-BOOK.”

Her little old red “Bible-book”

Lies here upon my stand,
So precious are its memories
I keep it close at hand.

Here on the fly-leaf is her name,

Long since ’twas written there,
Long ere she took the wander-road
In Sabbath-deeps of air.

How glad with gladness is the book,

Forever, ever new,
How dear with unforgetting love,
How sad with sadness, too.

The silver clasp is warped and worn,

And buckles with a lurch,
This Holy, Holy “Bible-book”
My mother took to church,

When I, a village six-year-old,

In dainty tier and frill,
Walked close beside, as hand in hand,
We climbed the steep, long hill.

There were no priests in white array,

How simple were the rites,
No lofty arch, no ruby glass,
Beadle nor acolytes,

But glory touched each sacred word,

 Love rippled like a brook,
As we together, side by side,
Read from this “Bible-book.”

Gone with the leaf and summer shine,

And youth, but even so,
How white and stainless is the page,
And O, how long ago

It seems since that immortal day!

But God, there is no smirch
On this—that Holy “Bible-book”
My mother took to church.
 MY FAITH.
I shall be fired with strength for that divine event—
The mightiest of life—
When these inspiring scenes, so beautiful,
Relinquish to that subtle and resistless spell
Which waiteth every man,
And every flower and leaf that grows.
I shall be given courage of a flying star,
The peerless chivalry of convoys of the air;
Half unaware I shall pursue my quest,
Same as a sea-bird mounts,
As light of wing;
The flush of morning in my face,
The flash that baffles minions of the dark,
The power that swung the constellations ’long the upper sky,
Impulse, like music, guiding me,
Song in my soul;
Still knowing I am loved, and love;
The friendly past,
The lifting present mine, as now,
I’ll not distrust,
And Life will not deceive me,
This I know.
 AN APOSTROPHE.

Old Plymouth is a rambling town,

And many leagues of beach there are,
Where echoes still the iron-sleet
And glows the crimson heart of war.

The smoke of battle pressing down

Still lurks where Liberty was bought,
And minute-men come pouring in,
Nor lust of power, or gold they sought.

Clear eyed they stand, of knotty arm,

O God of Fortune, Fate and Crown,
Make sure the bonds of brotherhood
’Twixt this old world and Plymouth-town.
 GLIMMER.
TO EUNICE.

Ever the witch in a school-girl’s eyes,

The toss and the flutter of flaxen hair,
The titter, and blush of a rosy cheek,
Are calling away from a world of care.

Leading the hours with a hop and a skip,

Down through a path where the wind-flowers grow,
White are the ribbons tied under her chin,
White are the ribbons that flutter and blow.

Ever the ring of a roguish laugh,

The swing of a rope, or a bonnet blue,
And a bright little band on a dainty hand,
Where twinkles a stone of a ruby hue,

Are daring me climb to the highest limb,

Or to jump the brook in a wild-fire race,
I’m as free and as light as the tail of a kite,
And I’ve two pouting lips for a resting place.
 A NOCTURNE.
How oft I feast with the dearest ones, now dead,
Or stroll the gardens through at night,
Indifferent to sleep.
’Tis then our footprints turn to gold,
For these are Love’s eternal hours,
That follow me in loneliness;
How often, when the leaves are listening,
I clasp white hands, I do not feel,
More delicate than touch of moonbeams in the grass;
’Tis then the thoughts arise like incense from a silver bowl.
We never hurry through the flowers,
Or miss the color of a dreaming rose,
Nor kiss too long.
But when the careless dawn comes whispering my name,
And seeking in the ashes grey, that once were fire,
We part;
And this is what has made the silences supreme.
 THE INVISIBLE.
The vast unconscious night hangs near and far,
Darkness born of day,
And sorrow born of joy;
But glowing everywhere is the tenderness of God,
Sun, moon and stars, and the living consciousness that I am I,
supreme;
A sense of nearness unto hidden mysteries that overreach the dark,
And claim my spirit as their own.
 ANTIPHONAL.
When I am gone the stones will talk of me,
The elm-trees speak together in the blast, as now,
And weep that I shall never more return;
And, be it that the dust shall grasp the throat of prayer, and strangle
it,
My hands, white-rising from the earth,
Will try again to sweep the lyre of song,
And quench the voice of death above my grave;
The day star in its flight will answer me.