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 Translational Immunology
TRANSLATIONAL AUTOIMMUNITY,
VOL. 5
 Translational Immunology
TRANSLATIONAL
AUTOIMMUNITY,
VOL. 5
Challenges for 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,
Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA),
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); School of Medicine; and
Research Center for Immunodeficiencies, Children’s Medical Center,
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.
 Contents

Contributors xi 3. Flow cytometry in the

Preface xv diagnosis of autoimmune-related
Series editor biography xvii lymphoproliferative disorder and
Acknowledgment xix lymphoma in the head and neck
Abbreviations xxi region
Lin (Jonathan) He, Franklin Fuda,
and Mingyi Chen
1. Introduction on challenges for
1 Introduction 18
autoimmune diseases
2 Representative histopathology,
Niloufar Yazdanpanah and Nima Rezaei
immunohistochemistry, and flow
cytometry 22
1 Introduction 1
3 Further discussion 30
2 Challenges in pathophysiology 2
4 Conclusion 33
3 Challenges in diagnosis 3
References 33
4 Challenges in treatment 4
5 Challenges in prevention 6
6 Conclusion 7
4. Autoantigens in atopic
References 7
dermatitis: The characterization
of autoantigens and their
2. From horror autotoxicus to diagnostic value
autoimmunity. An historical note Marlon Múnera, Andres Sanchez, Emiro Buendía,
Domenico Ribatti and Enrico Crivellato and Jorge Sanchez

1 Introduction 10 1 Introduction 37
2 Paul Ehrlich and the “horror autotoxicus” 10 2 Physiology of the skin 38
3 First evidence 11 3 Clinical characteristics of dermatitis; treatment
4 Autoimmunity in thyroid 11 and classification 39
5 Burnet and the prohibited clones 12 4 Molecular mimicry in atopic
6 Further evidence 12 dermatitis (AD) 40
7 Influence of HLA complex 13 5 Tools for the study and identification of
8 Vaccination and therapeutic approaches 14 autoantigens in atopic dermatitis 43
9 Criteria of definition and classification of 6 Particularities of type 2 immune response
autoimmune diseases 14 in atopic dermatitis 44
10 Conclusion 14 7 Conclusion 45
References 15 References 45

vii
viii Contents

5. Current paradigms of pathogenesis and 4 Kawasaki-like phenotype 94

challenges in vitiligo translational research 5 PIMS spectrum 94
6 Coronary artery aneurysm 95
Shahnawaz D. Jadeja, Ankit H. Bharti, Mitesh Dwivedi,
Jayvadan Vaishnav, Jay Mayatra, Ashwin Kotnis, Amina R. Gani, 7 Future directions 96
Naresh C. Laddha, and Rasheedunnisa Begum 8 Conclusion 97
References 98
1 Introduction 50
2 Understanding the pathogenesis of 8. Autoimmune conditions and epigenetic
vitiligo 51 challenges in periodontitis
3 Histopathology of vitiligo 53
Farah Asa’ad, Carlos Garaicoa-Pazmiño, and Lena Larsson
4 Current therapeutic modalities in vitiligo 55
5 Current translational research in vitiligo 61 1 Introduction 101
6 Current challenges and future therapeutic 2 Role of autoimmunity in periodontitis 102
avenues 65 3 Role of epigenetics in susceptibility
7 Conclusion 66 to periodontitis 105
References 67 4 Recommendations and future directions 111
5 Conclusion 114
6. The role of kynurenine pathway aryl References 114
hydrocarbon receptor axis in autoimmune
diseases of the skin 9. Neutrophil extracellular traps
Rowland Noakes in autoimmunity, renal diseases,
and transplantation
1 Introduction 79
Citlalin Vega-Roman, Zesergio Melo, and Raquel Echavarria
2 The kynurenine pathway 80
3 The aryl hydrocarbon receptor 80 1 Introduction 122
4 Autoimmune diseases 81 2 Mechanisms and function of neutrophil
5 The immune response in the skin 82 extracellular traps 122
6 Bullous pemphigoid 82 3 The role of NETs in autoimmunity 125
7 Systemic sclerosis 83 4 Clinical implications of neutrophil extracellular
8 Vitiligo 84 traps in renal diseases 127
9 Cutaneous disorders orchestrated 5 NETosis from the bench to the bedside 130
by interferons 85 6 Conclusion 132
10 Frontal fibrosing alopecia 86 References 132
11 Conclusion 87
References 87
10. Membranous nephropathy:
7. COVID-19 in childhood and phenotypes Clinical and immunological aspects
Israel Nieto-Gañán, Claudia Geraldine Rita, Ignacio Iturrieta-Zuazo,
of pediatric inflammatory multisystem and Ángela Carrasco-Sayalero
syndrome
Consolato M. Sergi 1 Introduction 139
2 Epidemiology 140
1 Introduction 91 3 Clinical aspects 141
2 COVID-19 92 4 Immunopathogenesis 142
3 Kawasaki disease 93 5 Diagnostics 152
 ix
Contents  

6 Treatment 156 4 Diagnosis 222

7 Conclusion 159 5 Treatment 226
References 159 6 Management of symptoms, extrahepatic
manifestations, and hepatocellular carcinoma 231
11. Testicular immune tolerance 7 Conclusion 234
and viral infections References 235
Sulagna Dutta, Pallav Sengupta, and Srikumar Chakravarthi
14. Modeling primary biliary cholangitis
1 Introduction 170
and primary sclerosing cholangitis as
2 Testicular immune privilege: Hide-out for virus 170
3 Anatomical basis of testicular immune infectious diseases
privilege 172 Kiandokht Bashiri, Stephen Ip, and Andrew L. Mason
4 Molecular basis of tolerogenic microenvironment
in the testis 172 1 Introduction 244
5 Common testicular viral infections 173 2 PBC 249
6 Testicular antiviral defense mechanism 175 3 PSC 261
7 Conclusion 177 4 Conclusion 270
References 177 References 270

12. Ophthalmological manifestations 15. Humoral epitope spreading

of systemic autoimmune diseases in autoimmune bullous diseases:
Marija Barišic Kutija An update
Dario Didona, Raffaele Dante Caposiena Caro, Luca Fania,
1 Introduction 183 Giovanni Paolino, and Biagio Didona
2 Rheumatoid arthritis 184
3 Primary Sjögren’s syndrome 189 1 Introduction 288
4 Seronegative spondyloarthropathies 192 2 Epitope spreading: Definition 288
5 Juvenile idiopathic arthritis 194 3 Epitope spreading: Mechanisms 289
6 Systemic lupus erythematosus 198 4 Epitope spreading in autoimmune bullous
7 Giant cell arteritis 203 diseases 290
8 Granulomatosis with polyangiitis 205 5 Conclusion 304
9 Multiple sclerosis, optic neuritis, References 304
and seropositive optic neuritis 205
10 Graves’ disease 208 16. Dermatologic autoimmunity
11 Conclusion 211
References 211
associated with immune checkpoint
inhibitors
Yannick S. Elshot, Siebe G. Blok, Marcel W. Bekkenk,
13. Challenges for diagnosis and treatment and Tiago R. Matos
of primary biliary cholangitis
Atsushi Tanaka 1 Introduction 312
2 Immune checkpoint inhibitors 314
1 Introduction 215 3 Autoimmunity 316
2 Epidemiology 216 4 Conclusion 323
3 Etiology 218 References 324
x Contents

17. Insights and strategies to promote 18. The potential of cellular

immune tolerance in allogeneic transplantation to harness autoimmunity
hematopoietic stem cell transplantation and reverse clinical diabetes
recipients Kevin Verhoeff and A.M. James Shapiro
Govindarajan Thangavelu, Sara Bolivar-Wagers, Ethan G. Aguilar,
Stephanie Y. Rhee, Brent H. Koehn, Keli L. Hippen, 1 Introduction 362
and Bruce R. Blazar 2 Islet cell transplant 368
3 Islet cell regeneration and immune reset 374
1 Introduction 330 4 Novel approaches to immunosuppression 376
2 Acute GVHD 330 5 Conclusion 378
3 Chronic GVHD 333 References 379
4 Tolerance 335
5 Tissue tolerance and reparative processes 346
6 Conclusion 347
References 347 Index 387
 Contributors
Ethan G. Aguilar Division of Blood and Marrow
Transplantation, Department of Pediatrics,
Masonic Cancer Center, University of Minne-
sota, Minneapolis, MN, United States
Farah Asa’ad Department of Biomaterials,
Institute of Clinical Sciences, The Sahlgrenska
Academy, University of Gothenburg, Göteborg,
Sweden
Kiandokht Bashiri Center of Excellence for
Gastrointestinal Inflammation and Immunity
Research; Division of Gastroenterology and
Hepatology, University of Alberta, Edmonton,
AB, Canada
Rasheedunnisa Begum Department of Biochem-
istry, Faculty of Science, The Maharaja Sayajirao
University of Baroda, Vadodara, Gujarat, India
Marcel W. Bekkenk Department of Dermatol-
ogy, Amsterdam UMC, University of Amster-
dam, the Netherlands
Ankit H. Bharti Dr. Ankit’s Dermatopathology
Research Centre, Vyara, Gujarat, India
Bruce R. Blazar Division of Blood and Marrow
Transplantation, Department of Pediatrics,
Masonic Cancer Center, University of Minne-
sota, Minneapolis, MN, United States
Siebe G. Blok Department of Dermatology,
Amsterdam UMC, University of Amsterdam,
the Netherlands
Sara Bolivar-Wagers Division of Blood and
Marrow Transplantation, Department of
­Pediatrics, Masonic Cancer Center, University
of Minnesota, Minneapolis, MN, United States
Emiro Buendía Faculty of Medicine, University
of Cartagena; Department of Internal Medicine,
Serena del Mar Hospital Center, Cartagena,
Colombia
Raffaele Dante Caposiena Caro Department of
Dermatology; Department of Systems Medicine,
University of Rome Tor Vergata, Rome, Italy
xi
Ángela Carrasco-Sayalero Immunology Depart-
ment, University Hospital Ramón y Cajal,
Madrid, Spain
Srikumar Chakravarthi School of Medical
Sciences, Bharath Institute of Higher Educa-
tion and Research (BIHER), Chennai, India;
Department of Pathology, Faculty of Medicine,
Bioscience and Nursing, MAHSA University,
Jenjarom, Selangor, Malaysia
Mingyi Chen Department of Pathology, UT
Southwestern Medical Center, Dallas, TX,
United States
Enrico Crivellato Department of Medicine,
Section of Human Anatomy, University of
Udine, Udine, Italy
Biagio Didona Department of Dermatology,
IDI-IRCCS, Rome, Italy
Dario Didona Department of Dermatology and
Allergology, Philipps University, Marburg,
Germany
Sulagna Dutta Department of Oral Biology
and Biomedical Sciences, Faculty of Den-
tistry, MAHSA University, Jenjarom, Selangor,
Malaysia; School of Medical Sciences, Bharath
Institute of Higher Education and Research
(BIHER), Chennai, India
Mitesh Dwivedi C. G. Bhakta Institute of Bio-
technology, Faculty of Science, Uka Tarsadia
University, Surat, Gujarat, India
Raquel Echavarria CONACyT-Western Biomed-
ical Research Center, Mexican Institute of Social
Security, Guadalajara, Jalisco, Mexico
Yannick S. Elshot Department of Dermatol-
ogy, Amsterdam UMC, University of Amster-
dam; Department of Dermatology, The
Netherlands Cancer Institute, Amsterdam,
The Netherlands
Luca Fania Department of Dermatology, IDI-
IRCCS, Rome, Italy
xii Contributors
Franklin Fuda Department of Pathology, UT
Southwestern Medical Center, Dallas, TX,
United States
Israel Nieto-Gañán Immunology Department,
University Hospital Ramón y Cajal, Madrid,
Spain
Amina R. Gani Department of Biochemistry,
Faculty of Science, The Maharaja Sayajirao
University of Baroda, Vadodara, Gujarat, India
Carlos Garaicoa-Pazmiño Department of Peri-
odontics, University of Iowa College of Den-
tistry, Iowa City, IA, United States; School of
Dentistry, Espiritu Santo University, Sambo-
rondon, Ecuador
Lin (Jonathan) He Department of Pathology,
UT Southwestern Medical Center, Dallas, TX,
United States
Keli L. Hippen Division of Blood and Marrow
Transplantation, Department of Pediatrics,
Masonic Cancer Center, University of Minne-
sota, Minneapolis, MN, United States
Stephen Ip Division of Gastroenterology and
Hepatology, University of Alberta, Edmonton,
AB, Canada
Ignacio Iturrieta-Zuazo Immunology Depart-
ment, University Hospital Ramón y Cajal,
Madrid, Spain
Shahnawaz D. Jadeja Department of Biochem-
istry, Faculty of Science, The Maharaja S
­ ayajirao
University of Baroda, Vadodara, Gujarat, India
A.M. James Shapiro Department of Surgery
and Clinical Islet Transplant Program, Univer-
sity of Alberta, Edmonton, AB, Canada
Brent H. Koehn Division of Blood and Marrow
Transplantation, Department of Pediatrics,
Masonic Cancer Center, University of Minne-
sota, Minneapolis, MN, United States
Ashwin Kotnis Department of Biochemistry,
All India Institute of Medical Sciences, Bhopal,
Madhya Pradesh, India
Marija Barišić Kutija Department of Ophthal-
mology, University Hospital Centre Zagreb,
Zagreb, Croatia
Naresh C. Laddha In Vitro Speciality Lab Pvt.
Ltd., Ahmedabad, Gujarat, India
Lena Larsson Department of Periodontology,
Institute of Odontology, The Sahlgrenska
Academy, University of Gothenburg, Göteborg,
Sweden
Andrew L. Mason Center of Excellence for
Gastrointestinal Inflammation and Immunity
Research; Division of Gastroenterology and
Hepatology, University of Alberta, Edmonton,
AB, Canada
Tiago R. Matos Department of Dermatology,
Amsterdam UMC, University of Amsterdam,
the Netherlands
Jay Mayatra Department of Biochemistry,
Faculty of Science, The Maharaja Sayajirao
University of Baroda, Vadodara, Gujarat,
India
Zesergio Melo CONACyT-Western Biomedical
Research Center, Mexican Institute of Social
Security, Guadalajara, Jalisco, Mexico
Marlon Múnera Medical Research Group
(GINUMED), Universitary Corporation Rafael
Nuñez, Cartagena, Colombia
Rowland Noakes Queensland Institute of Der-
matology, South Brisbane, QLD, Australia
Giovanni Paolino Unit of Dermatology, IRCCS
San Raffaele Hospital, Milano; Department of
Dermatology, University of Rome La Sapienza,
Rome, Italy
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
Stephanie Y. Rhee Division of Blood and
Marrow Transplantation, Department of Pedi-
atrics, Masonic Cancer Center, University of
Minnesota, Minneapolis, MN, United States
Domenico Ribatti Department of Basic Medical
Sciences, Neurosciences and Sensory Organs,
University of Bari Medical School, Bari, Italy
Claudia Geraldine Rita Immunology Depart-
ment, University Hospital Ramón y Cajal,
Madrid, Spain
 Contributors
Andres Sanchez Medical Research Group
(GINUMED), Universitary Corporation
Rafael Nuñez, Cartagena; Group of Clinical
and Experimental Allergy (GACE), IPS Uni-
versitaria, University of Antioquia, Medellín,
Colombia
Jorge Sanchez Group of Clinical and Exper-
imental Allergy (GACE), IPS Universitaria,
University of Antioquia, Medellín, Colombia
Pallav Sengupta School of Medical Sciences,
Bharath Institute of Higher Education and
Research (BIHER), Chennai, India; Department
of Physiology, Faculty of Medicine, Bioscience
and Nursing, MAHSA University, Jenjarom,
Selangor, Malaysia
Consolato M. Sergi Anatomic Pathology, Chil-
dren’s Hospital of Eastern Ontario, University
of Ottawa, Ottawa, ON; Stollery Children’s
Hospital, University of Alberta, Edmonton,
AB, Canada
Atsushi Tanaka Department of Medicine, Teikyo
University School of Medicine, Tokyo, Japan
xiii
Govindarajan Thangavelu Division of Blood
and Marrow Transplantation, Department of
Pediatrics, Masonic Cancer Center, University
of Minnesota, Minneapolis, MN, United States
Jayvadan Vaishnav Department of Biochemis-
try, Faculty of Science, The Maharaja Sayajirao
University of Baroda, Vadodara, Gujarat, India
Citlalin Vega-Roman Physiology Department,
CUCS, The University of Guadalajara; Sur-
gical Research Division, Western Biomedical
Research Center, Mexican Institute of Social
Security, Guadalajara, Jalisco, Mexico
Kevin Verhoeff Department of Surgery and
Clinical Islet Transplant Program, University
of Alberta, Edmonton, AB, Canada
Niloufar Yazdanpanah School of Medicine;
Research Center for Immunodeficiencies,
Children’s Medical Center, Tehran University
of Medical Sciences; Network of Immunity
in Infection, Malignancy and Autoimmunity
(NIIMA), Universal Scientific Education and
Research Network (USERN), Tehran, Iran
 Preface
The scientific world has witnessed remark-
able developments in the field of immunology
during recent decades. Novel discovery of
genes related to different ­immune-mediated
diseases has enhanced our knowledge about
the immune system and its interactions with
other systems in the human body and en-
lightened different aspects of its complexity
that lead to promoting diagnostic strategies,
designing more efficient therapeutic agents,
and reducing potential morbidities and mor-
tality. Due to the broad spectrum of immune-­
mediated diseases, from immunodeficiency
to hypersensitivity and autoimmune diseases,
the immune system diseases collectively con-
tribute to a considerable prevalence, although
every single immune-­mediated disease rep-
resents a low prevalence.
The responsibility of applying the lat-
est research findings had long been a con-
cern for scientists. Translational research is
recognized as a potential tool to utilize sci-
entific findings in clinical settings and pa-
tients’ care. Considering the wide spectrum
xv
of ­diseases related to the immune system
besides the huge burden for individuals,
health care settings, families, and society,
identifying promising alternative diagnostic
and therapeutic strategies through transla-
tional 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: Challenges for
Autoimmune Disease explores the existing
challenges in the pathophysiology, diagno-
sis, treatment, prognosis, and prevention of
autoimmune diseases. Challenges in each of
these aspects potentially challenge the oth-
ers, highlighting the importance of transla-
tional studies on autoimmune diseases. For
instance, challenges in identifying the de-
tails of the pathophysiology of autoimmune
diseases, including the genetic background
and the triggering factors, affect the devel-
opment of diagnostic tools and treatments.
Meanwhile, the prognosis of patients is af-
fected since it is linked to the administered
treatments. Taken together, detecting chal-
lenges in the field of autoimmune diseases
and designing strategies to tackle them
could have a remarkable effect on the pa-
tients’ quality of life, quality of the disease
management, and the overall burden of the
disease.
xvi Preface
This book begins with an introduction
to the challenges in different aspects of
­autoimmune diseases in Chapter 1. Chapter 2
focuses on a part of the history of autoim-
mune diseases and the challenges in the iden-
tification of these conditions. Chapters 3 and
4 dive deep into the challenges in the appli-
cation of some of the diagnostic tools of auto-
immune diseases. In addition, Chapters 5 and
6 are devoted to challenges in the research
path in the field of cutaneous autoimmune
diseases, an important group of autoim-
mune diseases. Chapter 7 emphasizes the
possibility of autoimmunity following newly
emerged diseases, by discussing the pediat-
ric inflammatory multisystem syndrome
following COVID-19, which raised concerns
for pediatric health since the start of the pan-
demic. In addition, some contributors to the
pathophysiology of autoimmune diseases
are explored in Chapters 8 and 9, to highlight
the challenges in the ­ pathophysiology of
­autoimmune diseases. Chapters 10–15 take
a focused view on the challenges that exist
in autoimmune diseases targeting different
tissues. Finally, Chapters 16–18 discuss some
important challenges in the treatment of au-
toimmune 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 in 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 spent a short-term
xvii
fellowship in 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 director of more than 50 research proj-
ects and has designed and participated in
several international collaborative projects.
Professor Rezaei is an editorial assistant and
board member for more than 30 interna-
tional journals. He has edited more than 30
international books, presented more than 500
lectures/posters in congresses/meetings,
and published more than 1000 scientific pa-
pers in international journals.
 Acknowledgment

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

Nima Rezaei, MD, PhD

xix
 Abbreviations

2-OADC 2-oxo-acid dehydrogenase complex BMSC bone marrow-derived hematopoietic

AAV ANCA-associated vasculitis and mesenchymal stem cells
ABDs autoimmune bullous diseases BMZ basal membrane zone
AC anterior chamber BNP B-type natriuretic peptide
ACE angiotensin converting enzyme BOP bleeding on probing
ACPA IgG anticitrullinated proteins BP bullous pemphigoid
antibodies BSA bovine serum albumin
ACTH adrenocorticotropic hormone BTB blood-testis barrier
AD atopic dermatitis CA cholangitis activity
ADs autoimmune diseases CAA coronary artery aneurysms
AEs adverse events CAL clinical attachment level
aGVHD acute graft-vs-host disease cAMP 3′,5′‐cyclic adenosine monophosphate
AHR aryl hydrocarbon receptor CAR chimeric antigen receptor
AHRNT aryl hydrocarbon receptor nuclear cART combination antiretroviral therapy
transporter CD celiac disease
AHRR aryl hydrocarbon receptor repressor CD cluster of differentiation
AHSCT autologous hematopoietic stem cell CGM continuous glucose monitoring
transplantation cGVHD chronic graft-vs-host disease
AIH autoimmune hepatitis CKD chronic kidney disease
AKI acute kidney injury CLL chronic lymphocytic leukemia
ALBIA addressable laser bead immunoassay CNI calcineurin inhibitors
allo-HSCT allogeneic hematopoietic stem cell CNS central nervous system
transplantation CNSDC chronic nonsuppurative destructive
ALP alkaline phosphatase cholangitis
AMA antimitochondrial antibodies COL17 type XVII collagen
AMP antimicrobial peptides COVID-19 coronavirus disease 2019
ANA antinuclear antibodies CP chronic periodontitis
ANA antinuclear antibody CRP complement regulatory protein
ANCAs antineutrophil cytoplasm antibodies CRP C-reactive protein
anti-CCP anticyclic citrullinated peptide CSII continuous subcutaneous insulin
anti-TPO thyroid peroxidase antibodies infusion
AP-1 activator protein 1 CTLA-4 cytotoxic T-lymphocyte-associated
APASL Asian Pacific Association for the Study antigen 4
of the Liver CTLD C-type lectin-like domain
APCs antigen-presenting cells CVD cardiovascular disease
APS autoimmune polyglandular syndrome CVID common variable immunodeficiency
AQP4 aquaporin-4 CYP1B1 cytochrome P450 1B1
ARG1 arginase-1 CysR N-terminal cysteine rich domain
AS ankylosing spondylitis DAF decay-accelerating factor
BAFF B-cell activating factor DAMPs damage-associated molecular patterns
Bcl-2 B-cell lymphoma 2 DC dendritic cells
BCOADC-E2 branched chain 2-oxoacid dDC dermal dendritic cells
dehydrogenase complex-E2 subunit DED dry eye disease
BEC biliary epithelial cells DEJ dermo-epidermal junction
BLL benign lymphoepithelial lesion DH dermatitis herpetiformis

xxi
xxii Abbreviations

DIF direct immunofluorescence GM-CSF granulocyte-macrophage colony

DLBCL diffuse large B-cell lymphoma stimulating factor
DM diabetes mellitus GMP good manufacturing practice
DMARD disease-modifying antirheumatic drug GN glomerulonephritis
DNMTs DNA methyltransferases GPA granulomatosis with polyangiitis
Dsg desmoglein GPCR GP40 G-protein–coupled receptor
E3BP dihydrolipoamide dehydrogenase- GVL graft vs leukemia
binding protein GWAS genome-wide association studies
EAE experimental autoimmune H&E hematoxylin and eosin
encephalomyelitis HA hepatitis activity
EASI Eczema Area and Severity Index HAT histone acetyltransferases
EBA epidermolysis bullosa acquisita HBV hepatitis B virus
EBV Epstein–Barr virus HCC hepatocellular carcinoma
EC extracellular HDAC histone deacetylases
eCIRP extracellular cold-inducible RNA- HDACi histone deacetylase inhibitor
binding protein HEK human embryonic cell
eFHSC epithelial follicular hair stem cells hESC human embryonic stem cells
EGFR epidermal growth factor receptor HIV human immunodeficiency virus
EGPA eosinophilic granulomatosis with HLA human leukocyte antigens
polyangiitis HSCT hematopoietic stem cell transplantation
ELISA enzyme-linked immunosorbent assay HSP heat shock proteins
EMBL European Molecular Biology IBAT ileal bile acid transporter
Laboratory IBD inflammatory bowel diseases
EndMT endothelial-to-mesenchymal transition IBMIR instant blood-mediated inflammatory
ER endoplasmic reticulum reaction
ER estrogen receptor ICA islet cell antibodies
ERT enzyme replacement therapy ICI immune checkpoint inhibitors
ES epitope spreading ICOS inducible costimulator
ESRD end-stage renal disease ICT islet cell transplantation
EV extracellular vesicles IDO indoleamine 2,3 dioxygenase
FABPs fatty acid–binding proteins IEQ islet equivalents
FasL Fas ligand IFN interferon
FC flow cytometry Ig immunoglobulin
FcЄR1 high-affinity receptor for the Fc region IgG4-RD IgG4-related disease
of immunoglobulin E IgG4-RS IgG4-related sialadenitis
FDA Food and Drug Administration IHC immunohistochemistry
FDA US Food and Drug Administration IIF indirect immunofluorescence
FFA free fatty acids IL interleukin
FICZ 6-formylindolo [3,2-b] carbazole ILCs innate lymphoid cells
FISH fluorescence in situ hybridization IMN idiopathic membranous nephropathy
FL follicular lymphoma iNKT invariant natural killer T
FNA fine needle aspiration IP-10 IFN-y–inducible protein 10 kDa
FnII fibronectin type 2 domain IPEX immune-dysregulation
Foxp3 forkhead box P3 polyendocrinopathy enteropathy
FXR farnesoid X receptor X-linked
GABA gamma-aminobutyric acid iPSC inducible pluripotent stem cells
GAD 65 glutamic acid decarboxylase 65 IrAEs immune-related adverse effects
GBM glomerular basement membrane IRF interferon regulatory factor
GCA giant cell arteritis ISC intestinal stem cells
GCF gingival crevicular fluid ISH in situ hybridization
GCN2 general control nonderepressible 2 ITGAM integrin subunit alpha M
GCSF granulocyte colony-stimulating factor ITIM immunoreceptor tyrosine inhibitory
GIP glucose-dependent insulinotropic motif
peptide iTregs inducible Tregs
GLP-1 glucagon‐like peptide 1 IVIG intravenous immunoglobulin
 Abbreviations xxiii
IVMP intravenous methylprednisolone MUM-1 multiple myeloma oncogene-1
JAK Janus kinase MZL marginal zone lymphoma
JIA juvenile idiopathic arthritis NAD nicotinamide adenine dinucleotide
KATP ATP-dependent potassium channels NAG N-acetyl-β-d-glucosaminidase
KIM-1 kidney injury molecule 1. NBS-LRR nucleotide-binding site leucine-rich
KP Kynurenine pathway repeat
KP/AHR kynurenine-pathway/aryl hydrocarbon NE neutrophil elastase
receptor NEP antigen neutral endopeptidase
LABD linear IgA bullous dermatosis NETs neutrophil extracellular straps
Lag3 lymphocyte activation gene 3 NETs neutrophil extracellular trap
LDGs low-density granulocytes NF-κB nuclear factor kappa light chain
LESA lymphoepithelial sialadenitis enhancer of activated B cells
LN lupus nephritis NGAL neutrophil gelatinase-associated
LP lichen planus lipocalin
LPA lysophosphatidic acid NHANES National Health and Nutrition
LPD lymphoproliferative disease Examination Survey
LPP lichen planus pemphigoides NHL non-Hodgkin lymphoma
LPS lipopolysaccharides NK natural killer
LT liver transplantation NLRP3 nucleotide-binding oligomerization
LTBP latent TGF-β binding proteins domain-like receptor family pyrin
Lyso-GPC lyso-glycerophosphatidylcholines domain containing 3
M3AchR β‐cell muscarinic receptors NLRs nucleotide-binding oligomerization
mAbs monoclonal antibodies domain-like receptors, or NOD-like
MAC membrane attack complex receptors
MALT mucosa-associated lymphoid tissue NMDA anti-N-methyl d-aspartate
MAPK mitogen-activated protein kinase NMO neuromyelitis optica
MAS macrophage activation syndrome NO nitric oxide
MAS multiple autoimmune syndromes NOD nonobese diabetic
MBL mannan-binding lectin NOX NADPH oxidase
MBP myelin basic protein Nrf2 nuclear factor erythroid-derived 2, like
MCP membrane cofactor protein 2 transcription factor
MCP-1 monocyte chemotactic protein-1 nRNP nuclear ribonucleoproteins
mDCs myeloid dendritic cells NSAID nonsteroidal antiinflammatory drug
MDSCs myeloid-derived suppressor cells NT-proBNP N-terminal (NT)-prohormone BNP
MFI median fluorescence intensity nTreg natural regulatory T cell
MGD meibomian gland dysfunction OCA obeticholic acid
MHC major histocompatibility complex OGDC-E2 2-oxo-glutamic acid dehydrogenase
MHD maintenance hemodialysis complex-E2 subunit
MIG monokine induced by IFN-y OLP oral lichen planus
miR microRNA ON optic neuritis
MMF mycophenolate OPG osteoprotegerin
MMF mycophenolate mofetil OR odds ratio
MMP mucous membrane pemphigoid OxLDL oxidized low-density proteins
MMPs metalloproteinases OXPHOS oxidative phosphorylation
MN membranous nephropathy P2X7 P2X purinoreceptor 7
MnSOD manganese superoxide dismutase p38MAPK p38 mitogen-activated protein kinase
MPA microscopic polyangiitis PAD peptidylarginine deiminase
MPO myeloperoxidase PAI1 plasminogen activator inhibitor type 1
mRNA messenger RNA PAMPs pathogen-associated molecular patterns
MS multiple sclerosis PBC primary biliary cholangitis
MSC mesenchymal stem cells PCR polymerase chain reaction
MSP-PCR methylation-specific polymerase chain PD probing depth
reaction PD-1 programmed death-1
mTOR mammalian target of rapamycin PDC-E2 pyruvate dehydrogenase complex-E2
MTX methotrexate subunit
xxiv Abbreviations

pDCs plasmacytoid dendritic cells SM Smith antigen

PD-L1 programmed death ligand-1 SMN secondary membranous nephropathy
PF pemphigus foliaceus SNP single-nucleotide polymorphism
PICF peri-implant crevicular fluid SpA spondyloarthropathy
PIMS pediatric inflammatory multisystem SR steroid refractory
syndrome SS Sjögren’s syndrome
PKA protein kinase A STAT signal transducer and activator of
PLA2R M-type phospholipase A2 receptor transcription proteins
PMA phorbol 12-myristate 13-acetate T1DM type 1 diabetes mellitus
PMN polymorphonuclear leukocytes TAO thyroid-associated ophthalmopathy
PPAD Porphyromonas gingivalis TCD T-cell depletions
peptidylarginine deiminase TCDD tetrachlorodibenzoparadioxin
PPAR‐γ peroxisome proliferator‐activated Tcons T conventional
receptor gamma TCR T-cell receptor
PR3 proteinase 3 Teffs T effectors
PRR pattern recognition receptors TEN Stevens-Johnson syndrome (SJS) or
PSC primary sclerosing cholangitis toxic epidermal necrolysis
pSS primary Sjögren’s syndrome TEWL transepidermal water loss
PTLD posttransplant lymphoproliferative TF tissue factor
disorder Tfh T follicular helper cells
pTregs peripheral Tregs TGF transforming growth factor
PV pemphigus vulgaris Th T helper cells
RA rheumatoid arthritis THSD7A thrombospondin type-1 domain-
RAAS renin-angiotensin-aldosterone system containing 7A
rAAV adeno-associated virus Tim-3 T-cell immunoglobulin mucin-3
RANKL receptor activator of nuclear factor TIMPs tissue inhibitors of MMPs
kappa B ligand TJ tight junctions
RBP retinol-binding protein. TLR toll-like receptors
RF rheumatoid factor TMPRSS2 transmembrane protease serine 2
rhASB recombinant arylsulfatase B TNF tumor necrosis factor
rhGAA recombinant Human alpha-glucosidase Tr1 T regulatory type 1
RLRs retinoic acid-inducible gene I (RIG-I)- TR1 Type 1 regulatory T cells
like receptors TRAIL TNF-related apoptosis-inducing ligand
RNFL retinal nerve fiber layer Treg regulatory T-cells
ROS reactive oxygen species TRP tyrosinase-related protein
RR relative risk ratio TSLP thymic stromal lymphopoietin
RTX Rituximab tTG tissue transglutaminase
SAMHD1 sterile-α-motif and HD domain- tTreg thymus regulatory T cell
containing protein 1 tTregs thymic derived Tregs
SARS-CoV severe acute respiratory syndrome UCB umbilical cord blood
coronavirus UDCA ursodeoxycholic acid
SCARs severe cutaneous adverse reactions UPR unfolded protein response
scfa short chain fatty acids VEGF vascular endothelial growth factor
SCID severe combined immune deficiency VISTA V-domain Ig suppressor of T-cell
SCORAD severity scoring atopic dermatitis activation
SE shared epitope XAP2 hepatitis B virus X–associated protein 2
SHM somatic hypermutation XRE xenobiotic response elements
SIB Swiss Institute of Bioinformatics α-GalCer alpha-galactosylceramide
SLE systemic lupus erythematosus α-MSH alpha melanocyte stimulating
SLL small lymphocytic lymphoma hormone
 C H A P T E R

1
Introduction on challenges
for autoimmune diseases
Niloufar Yazdanpanaha,b,d and Nima Rezaeib,c,d,⁎
a
School of Medicine, Tehran University of Medical Sciences, Tehran, Iran bResearch Center for
Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran,
Iran cDepartment of Immunology, School 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
Autoimmune diseases have remained a mysterious territory in medical sciences. Considering the unanswered
questions concerning the ethiopathogenesis of autoimmune diseases, many challenges remained to be tack-
led in this field. The prevention, diagnosis, treatment, and prognosis of autoimmune diseases are affected by
different factors; for instance, the specificity and sensitivity of most diagnostic tools as well as the therapeutic
agents do not meet the expectations, while there is no validated marker for disease prediction or prognosis.
Nevertheless, new fields of research including multiomics analysis, immunometabolism, genetic studies, and
precision medicine could be promising tools to address the existing challenges in autoimmune diseases.

Keywords
Autoimmune, Autoimmunity, Challenges, Pathophysiology, Diagnosis, Treatment, Prevention

1 Introduction

Autoimmune diseases are known as the consequence of the immune system’s misrecogni-
tion of self-antigens as harmful. About 5%–8% of the world population suffers from autoim-
mune diseases [1]; meanwhile, due to the need for a prolonged period of treatment, life-long
treatment in some cases, autoimmune diseases impart a remarkable burden to the healthcare
system and affect the countries’ socioeconomic status. Being studied for decades, many ques-
tions about autoimmune diseases remained to be addressed.

Translational Autoimmunity, Vol. 5 1 Copyright © 2023 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/B978-0-323-85389-7.00014-4
 1. Challenges in autoimmune diseases

Diagnosis of autoimmune diseases is based on clinical assessment besides laboratory testing,

which mainly aims to detect autoantibodies in the body fluids and/or tissues. Nevertheless,
these antibodies are not specific in some cases or cannot be detected prior to the disease manifes-
tations. On the other hand, in most cases, the diagnosis is made after excluding other conditions
that could manifest the patient’s symptoms. Therefore, designing a proper diagnostic method
for autoimmune diseases is of interest. Blood testing remains the mainstay in the diagnosis
process and follow-up of patients; however, searching for novel more sensitive and specific
markers might help accelerate and optimize the diagnosis process of autoimmune diseases.
The treatment armamentarium of autoimmune diseases mainly comprises nonspecific and
broad-spectrum therapeutic agents that modulate the immune system. Treatment of patients
with autoimmune diseases commonly goes through a trial-and-error manner; the treatment
regimen escalates to newer drugs when the patient fails to respond to the already adminis-
tered ones. Hence, patients receive a wide variety of therapeutic agents during their course of
treatment, which predispose them to different complications and comorbidities triggered by
the adverse effects of administered treatment. Recent decades have witnessed vast research
aiming to find the proper treatment for autoimmune diseases. Translating the findings of
basic science research on the molecular and cellular mechanisms of autoimmunity and the
underlying genetic defects and susceptibility loci to drug design measures could optimize
this process. Moreover, drug repurposing could be a promising method for finding proper
treatment options for autoimmune diseases.
There are different alternative treatment approaches proposed for autoimmune disease;
for instance, metabolic reprogramming of the underlying immune pathways of autoimmune
diseases and gene therapy.
Precision medicine and personalized medicine have become interesting areas of research
in autoimmune diseases. Considering the different manifestations and underlying defective
pathways of autoimmune diseases, personalized medicine could be helpful in these patients.
The concept of the application of personalized medicine in autoimmune diseases has under-
pinned the importance of multiomics research in the context of autoimmune diseases.
Treatment of autoimmune diseases has been always challenged by associated comorbid-
ities of autoimmunity such as malignancies and infections. The coexistence of malignancy
and autoimmunity seems paradoxical in treatment since reinforcing immune responses is the
strategy to combat malignancies, while immunomodulatory strategies are proposed in au-
toimmunity. In addition, the patient’s compliance to treatment the accurate use of drugs are
important factors in disease management concerning the necessity of prolonged or life-long
need for using drugs.
Diagnosis, treatment, follow-up, and prevention of autoimmune diseases have been al-
ways associated with different challenges. In this chapter, we aim to provide an overview of
the challenges that exist in autoimmunity research, translation of preclinical and laboratory
findings to the clinical setting, and management of the diseases.

2 Challenges in pathophysiology

Despite the significant development in understanding the pathophysiology of autoimmune

diseases, many questions remained unanswered in this field. Genes, the immune system, and
environmental factors are at play in the pathophysiology of autoimmunity. Genes create a

2
 Niloufar Yazdanpanah and Nima Rezaei

tendency in individuals to develop autoimmunity. The dysregulated immune system, either

due to a genetic defect or due to any other dysregulating process, is known as the main actor
in the autoimmunity process. Environmental factors unravel the autoimmune disease with
different triggers. Nevertheless, although the main players contributing to the unfolding of
autoimmune diseases are known, the network of the interactions of these factors remained to
be fully depicted. For instance, genetic factors in different autoimmune diseases do not follow
a same pattern. Although some autoimmune diseases are attributed to a specific gene (e.g.,
immune-dysregulation polyendocrinopathy enteropathy X-linked or IPEX syndrome that is
linked to FOXP3 mutation) [2], some are linked to a variety of genetic variants in different
loci (e.g., SLE) [3]. Nevertheless, there are some autoimmune diseases with unknown genetic
backgrounds. Unclarified pathophysiology of an autoimmune disease, in turn, challenges the
diagnosis, treatment, and prognosis of the disease.

3 Challenges in diagnosis

While in most cases the diagnosis of autoimmune disease is established according to the
initial organ involvement and the medical specialty that the patient is referred to, the con-
currence of two or more autoimmune diseases in the same patient and at the same time is
reported in 0.4%–0.5% of the global population diagnosed with autoimmune diseases [4]. It
is commonly reported in multiple sclerosis (MS), autoimmune thyroiditis, rheumatoid arthri-
tis (RA), type 1 diabetes mellitus (T1DM), inflammatory bowel disease (IBD), and vitiligo.
Two definitions, multiple autoimmune syndromes (MAS) and overlap syndromes, are made
to classify these conditions. Addison’s syndrome was the first case that introduced as an
integration of different autoimmune conditions, namely adrenal insufficiency, vitiligo, and
pernicious anemia [5]. MAS is used for conditions previously defined as autoimmune poly-
glandular syndrome (APS) [6]. This definition consists of both complete MAS and incomplete
MAS, of which incomplete subtypes are more common. For instance, detection of autoanti-
bodies related to other autoimmune diseases in a patient with one established autoimmune
condition is classified as incomplete MAS [7]. Overlap syndromes are known as conditions,
occurring in an individual at the same time or different periods, fulfilling the classification
criteria of at minimum two autoimmune diseases; this condition is mainly established in con-
nective tissue diseases and liver diseases [8,9]. Identification of MAS and overlap syndromes
and diagnosis of these conditions in the clinic could play an integral role in disease man-
agement, treatment, and prognosis. In addition, in cases of overlap syndromes, perdition of
the forthcoming autoimmune complications in a patient with an established diagnosis of an
autoimmune disease could help to prevent the progression of other associated autoimmune
complications by starting the treatment at early stages.
Progression of autoimmune diseases to the complete phenotype of the disease can take
weeks to months. Within this period, the level of autoantibodies undergoes a wax and wane
process [10]. Hence, autoantibodies alone could not be counted as a diagnostic method due to
their altered levels during the disease. In line with this, identification of novel biomarkers for
autoimmune diseases has been an interesting area of research. On the other hand, there are
some ethical issues with conducting vast case–control and cohort studies. For instance, in case,
a participant that enters the study without any preexisting autoimmune diseases and during

3
 1. Challenges in autoimmune diseases

the evaluation becomes positive for a marker that predicts a high risk of developing autoimmu-
nity, it is controversial whether it is ethical to induce anxiety and stress in a healthy participant
who may or may not develop the predicted disease. Application of genomics, proteomics, ri-
bonomics, and metabolomics research could be helpful in the recognition of new autoantigens,
autoantibodies, and biomarkers for autoimmune diseases [11]. Finding specific markers for au-
toimmune diseases potentially facilitates the diagnosis process since, currently, the diagnosis of
most autoimmune diseases is based on the exclusion of other medical conditions.

4 Challenges in treatment

Treatment of autoimmune diseases has been always faced different challenges. Currently,
widely available drugs for autoimmune diseases are nonspecific and associated with various
adverse effects. The treatment armamentarium of autoimmune diseases includes corticoste-
roids, immunomodulatory agents, and some limited cytotoxic drugs. However, extensive
research is ongoing to find novel specific therapeutic agents with limited adverse effects to
optimize the course of treatment. On the other hand, the associated complications of autoim-
munity, including malignancies and infections, challenge the treatment process. The role of
the patient in experiencing a successful course of treatment is undeniable. In the following
sections, we provide a comprehensive review of challenges concerning the treatment of au-
toimmune diseases.

4.1 Adverse effects

Steroids have been an important part of the treatment regimen for autoimmune diseases.
They block inflammation by inhibiting cytokine production, immune cells’ migration to in-
flammation sites, and by depleting immune cells such as T and B lymphocytes. Steroids are
associated with an increased risk of susceptibility to opportunistic infections due to the global
unspecific inhibition of different parts of the immune system. In addition, long-term use of
steroids affects the normal homeostasis of bones, impairs blood pressure and blood sugar,
and increases the risk of cataracts.
Diseases-modifying antirheumatic drugs (DMARDs) are another group of treatment can-
didates for autoimmune diseases. DMARDs consist of three main groups: conventional (csD-
MARDs), targeted synthetic (tsDMARDs), and biological (bDMARDs) [12]. These drugs, in
particular csDMARDs, have a wide range of effects on different parts of the immune system,
hence representing nonspecific inhibitory and immunomodulatory effects, which result in
lower efficacy than expected and different adverse effects. tsDMARDs act more specifically
and target some small molecules. bDMARDs that function with high specificity are monoclo-
nal antibodies or receptor constructs [12]. In the late 1970s, researchers observed an enhanced
rate of malignancies in patients receiving combination DMARD therapy (cyclophosphamide,
azathioprine, and hydroxychloroquine) [13]. In an attempt to reduce the adverse effects due
to the global inhibitory effect of prior medications and increase the efficacy of treatment, these
different types of DMARDs developed. Nevertheless, some adverse effects are still reported
in using these agents; for instance, almost all types of DMARDs are associated with increased
risk of infections and lung toxicity [14]. To increase the efficacy of treatment, biologic agents

4
 Niloufar Yazdanpanah and Nima Rezaei

have been applied as adjuncts to DMARDs. B cells, cytokines, costimulatory molecules, and
B cell receptors are the targets of biological agents. Although this type of targeted therapy is
properly tolerated in patients, they are not included in the first-line treatment options, due to
the route of administration (intravenous, which is not preferred by most of the patients) and
the high expenses [15].

4.2 Treatment of autoimmunity and cancer

Patients with autoimmune diseases have shown an increased tendency to develop ma-
lignancies [16]. Hence, the treatment of cancer in patients with a preexisting autoimmune
disease has been always challenging. A lower cancer survival rate is reported in patients
with autoimmune diseases than in the overall population [17,18], which could be attributed
to immune-related adverse effects (IrAEs) induced by anticancer treatment [15]. Hence, im-
mune biological cancer treatments could potentially exacerbate the autoimmune disease by
inducing IrAEs.

4.3 Metabolic reprogramming

Immune cells benefit from different nutrients and metabolic pathways according to their
function and level of differentiation, making immunometabolism a plastic process. In other
words, different immune cells prefer different metabolic pathways as their main route for
gaining energy [19]. For instance, while the dominant metabolic pathway in effector T cells
is glycolysis, oxidative phosphorylation is the most commonly observed metabolic pathway
in memory T cells [19]. Hence, metabolic reprogramming could be a promising approach for
the treatment of autoimmune diseases. This method is safe once the metabolism-modulating
drug is properly delivered to the targeted cells, and the sensitivity of nontarget cells is low at
the time of drug administration. A precise understanding of the underlying mechanisms in
autoimmune diseases and the mechanism of action of drugs could facilitate the drug repur-
posing process.

4.4 Stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is recommended for patients suffering
from refractory autoimmune diseases. It has been more commonly used for systemic sclerosis,
MS, RA, juvenile idiopathic arthritis, and systemic lupus erythematosus (SLE). Nevertheless,
due to the serious adverse effects, leading to a high rate of morbidity and mortality, it is not
used as the standard treatment of choice. Increased vulnerability to severe infections, cardiac
and renal toxicity, susceptibility to malignancies, and the risk of the emergence of autoimmu-
nity (a secondary autoimmune disease) are notable risks of HSCT [20,21].

4.5 Gene therapy

The introduction of gene transfer technology in 1990 [22] has attracted the attention of
scientists to the application of gene therapy in the treatment of different diseases. Although
most of the conducted works in this field are related to cancer, monogenic disorders, and

5
 1. Challenges in autoimmune diseases

c­ ardiovascular diseases, gene therapy approaches have been proposed for the treatment of
autoimmune diseases as well [23]. There are several reports concerning the positive effect
of gene therapy in reducing the severity of symptoms in autoimmune animal models. For
instance, Kok et al. observed that a recombinant adeno-associated virus (rAAV) vector which
coded IL-10 considerably improve the salivary glands pathological markers in Sjogren’s syn-
drome model in nonobese diabetic (NOD) mice [24]. Furthermore, besides viral vectors, T
cells and B cells have represented great promises in carrying genes for immunomodulatory
purposes. As an example, Guichelaar et al. reported that transferring the IL-10 gene by adop-
tive autoantigen-specific CD4+ T cells transfer could be a potentially effective approach to
compensate for the altered T cell regulation in mice with chronic arthritis [25]. Drawing a con-
clusion upon this perspective, genetic studies to identify the responsible genes in the patho-
physiology of autoimmune diseases and observational studies for recognizing biomarkers
could lead to choosing a proper target for gene therapy in autoimmune diseases. Meanwhile,
the application of siRNA, miRNA, and mesenchymal stem cells could provide novel oppor-
tunities for the treatment of autoimmune diseases.

4.6 Patient’s compliance

Besides different treatment approaches, an important factor to experience a successful
course of treatment is the patient’s compliance to the treatment. Due to the prolonged course
of treatment, life-long in some cases, it is important to keep the patient attached to the thera-
peutic program. Patients’ perception of the disease, acceptance of the disease and the recom-
mended treatment, cultural attitudes, and cognitive and interpersonal factors contribute to
the degree of patient adherence to the treatment [26]. In addition, the mental burden of being
ill for a long period of life or the whole life affects the patient’s compliance, influencing the
effectiveness of treatment [27].

5 Challenges in prevention

In burdensome medical conditions, prevention could be a reasonable strategy. To apply

the preventive strategies to combat autoimmune diseases, it is necessary to determine the
risk factors that are closely linked to autoimmune predisposition. Some identified genetic
susceptibility loci are predictive of developing autoimmune diseases in the future. On the
other hand, different autoantibodies are detectable in samples from patients years before the
onset of manifestations; for instance, anticyclic citrullinated peptide (anti-CCP) for RA, thy-
roid peroxidase antibodies (anti-TPO) for postpartum autoimmune thyroid disease, and anti-
nuclear antibodies (ANA) and anti-Ro antibodies for SLE. Detection of these autoantibodies
in a patient with genetic susceptibility to autoimmunity raises the possibility of developing
the autoimmune disease in the future. Furthermore, some medical conditions predispose
patients to autoimmune diseases. Patients with chronic infections, prolonged inflammatory
status, and primary immunodeficiency diseases have a high propensity for autoimmunity.
Recognizing autoimmunity-prone patients lead to early initiation of treatment, which poten-
tially reduces the risk of further complications and disease burden on the patient, family, and
the healthcare system [28,29].

6
 Niloufar Yazdanpanah and Nima Rezaei

6 Conclusion

Although the knowledge in the field of autoimmune diseases developed considerably

during the recent decades, many challenges remained to be tackled. Researches have put
enormous effort into finding proper diagnostic and treatment methods to improve the quality
of care and quality of life of patients. Studies on molecular mechanisms of autoimmunity and
translation of the results to clinical applications could promote the process of designing tools
and drugs.

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8
 C H A P T E R

2
From horror autotoxicus to
autoimmunity. An historical note
Domenico Ribattia,⁎ and Enrico Crivellatob
a
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari
Medical School, Bari, Italy bDepartment of Medicine, Section of Human Anatomy, University of
Udine, Udine, Italy
⁎
Corresponding author

Abstract
At the beginning of the 20th century, the knowledge on autoimmunity was very limited. In 1899, Jules Bordet
demonstrated that autoantibodies specific for erythrocytes could cause their own destruction in conjunction
with serum complement. In 1904, Julius Donath and Karl Landsteiner reported the first observation of a true
autoimmune disease, paroxysmal cold hemoglobinuria, a complement-dependent hemolytic anemia. They
demonstrated the presence of a lytic substance in the blood of three patients with paroxysmal cold hemoglo-
binuria. An autoimmune disease can generally be defined as one in which an autoantibody or a sensitized
lymphocyte reacts with host tissue. The prevalence of autoimmune diseases is significantly increasing in the
world population. We now recognize more than 80 clinically distinct human diseases that result at least in part
from an autoimmune response. Autoimmune diseases generally result from the association of genetic suscep-
tibility and environmental triggers. Infectious agents have long been the most well-studied environmental
factors. Despite the diversity in natural history and presentation, autoimmune diseases share a number of
underlying mechanisms. More selective and less toxic immunosuppressive and immunomodulatory agents
are used to treat these disorders, and promising immune tolerance approaches are emerging.

Keywords
Autoimmunity, Horror autotoxicus, History of immunology

Translational Autoimmunity, Vol. 5 9 Copyright © 2023 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/B978-0-323-85389-7.00006-5
Another random document with
no related content on Scribd:
 Perhaps you are older than some of your school-fellows,
and the little ones gather round you and say "Tell us a
story!"

Don't they love stories? And don't you love stories?

So did the people to whom our Lord spoke. He often put

a word-picture before their eyes, and it sank into their
hearts, and they remembered it ever after.

I am going to tell you about one of these Parables which

our Lord told to the listening multitudes.

This one was about "The Kingdom of Heaven." This is

the word picture which he put before their eyes.

He said that the Kingdom of Heaven was like a man who

had a field, and who sowed it with good seed.

But at night, under cover of the darkness, while men

were asleep, there came an enemy into this field.

He carried a basket in his hands, and as he went up and

down the field, he looked stealthily round him to make sure
that no one was aware of his presence. And then he took
handful after handful of seed from his basket and scattered
it all over the field. Then he crept away in the darkness.
 SOWING THE TARES.

Why did he do it, do you think?

It was because he hated the owner of the field, and

wished to destroy his beautiful harvest.

By and by the seeds began to grow, and the little blades

came up green all over the field. Then the servants of the
master of the field, looking closely at the crop, saw that
some of the blades were of good wheat, but some looked
like tares, which were of no use to anyone and only injured
the wheat. So they hastened to the owner of the field, and
they said, "Sir, did you not sow good seed in your field; how
have the tares got there?"

And the owner said, "An enemy has done this."

Then the servants asked if they might root up the tares

at once.

I have read that when the little plants are young, the
blades of the wheat and the blades of the tares are so much
alike that it is difficult to tell them apart.

So the master of the field answered, "No; you had

better not try to pull up the tares, lest you should pull up
the wheat with them. Let them both grow together until the
harvest; and in time of harvest I will say to the reapers,
'Gather together the tares first, and bind them in bundles to
burn them; but gather the wheat into my barn.'"

* * * * *

This is a story, as I said, of "The Kingdom of Heaven."

And it is important to all of us, because we all live in that
Kingdom. Our hearts ought to be God's throne here, we
ought to be growing up as His Good Seed, to be gathered
into His eternal Home when the Harvest comes!

You may not always live in England—you may go to

Canada, or Australia, or France, or Germany!

But in this Kingdom of Heaven you may always abide,

till the Harvest-day comes; and happy for you if you do!

God's Kingdom is a place where His Good Seed grows.

 Perhaps your Mother or your Teacher tells you of Jesus
our Saviour, and of His love, and you long to be able to
serve Him. You would like to be kind and loving to those
round you; you are sorry when you do wrong, you are
happy when you do right. That is the Good Seed taking root
and growing in your heart!

But at other times you feel differently.

You are not so happy; you do not wish to do good

things so much; you even find yourself wanting to do wrong
things! You find it hard to be loving; you want so much to
do something you have been forbidden to do; you are sure
no one will see you if you do wrong, and you say to
yourself, "After all, it is such a little thing," or "It is only this
once!"

Ah! Those are the tares sown in your heart!

"How did they get there?" the servants asked the

Master.

And He answered, "An enemy has done this."

Satan is our enemy. It is true we cannot see him, but

he is near us all the same.

Like the enemy in the Parable, he creeps out when men

are asleep—when you are off your guard—when you have
forgotten to watch and to pray; and it is he who whispers to
you that:

"No one will see."

"That it is such a little thing."

"That it is so hard to obey!"

 Ah! What must the little Christian boy do when he finds
tares in the field of his heart? What must the little Christian
girl do when she finds tares in God's Kingdom in her heart?

I think the best thing to do is to look up to Jesus

instantly, and ask Him to conquer the great enemy for you.
Say the Holy name Jesus softly to yourself, or out loud if
you are alone, Satan, our great enemy, will run away, you
will surely find.

He was named JESUS (which means Victory).

"For He shall save His people from their sins."

XXVIII. The Prodigal Son

There was a man who had two sons. He loved them

both very much, and did everything he could to make them
happy.

But the younger son was restless, and got tired of being
quietly at home. He had heard something about the world
outside, and he thought it must be a very fine place by all
accounts.

So one day he asked his father to divide what he had to

leave to him and his brother, so that he might do as he liked
with his share of it.
 Not many days after, the younger son took his journey
into a far country, and as he had no one there to guide him,
and as he did not heed the advice of his dear father, he
began to waste his money and get into evil ways.

Very soon he had spent all his father had given him,
and had nothing left in his purse.

Up to this time he had thought he could do very well

without his father, but now he began to be in want. It was
so hard to be hungry, to find his clothes get ragged, and for
his companions to forsake him. And it made him sad and
afraid when he remembered that he had no house to sleep
in, and no friends near.

By and by a farmer took pity on him, and hired him to

go and feed his pigs; and he was so hungry that he could
almost have eaten the pigs' food. But no one gave him
anything.

At last as he sat dejectedly watching the pigs, he came

to himself! He began to remember his dear home and his
father's love. He no longer prided himself on what he could
do, and what he could buy. He saw his behaviour in its true
light. He told himself that he had been very naughty and
very disobedient, and he began to be sorry.

And when he came to himself he said, "How many of

my father's hired servants have bread enough and to spare,
and I, his son, am dying of hunger! I will arise and go to my
father, and tell him I have sinned, and ask him to make me
one of his servants."

So he got up to go to his father.

His father had been very sad all the time his boy had
been away. His heart had ached terribly, though his son had
never thought of that.

Every day he looked out for his lost one, and watched
for him along the roads and over the mountains till it grew
too dark to see.

But one day, when the son was yet a great way off, his
father saw him coming! Then the dear father ran to meet
him, and fell on his neck and kissed him.

And the son said, "Father, I have sinned before Heaven

and in thy sight, and am no more worthy to be called thy
son—"

But he could not get any further than that in what he

meant to say! For his father's arms were round him, and his
father's voice was saying in the old familiar tones, "Bring
hither the best robe, and put it on him! And put a ring on
his hand, and shoes on his feet; and bring here the fatted
calf and let us make a feast; for this my son was dead, and
is alive again; he was lost, and is found!"

Children, we have here a picture of the way our loving

Heavenly Father welcomes back those who have wandered
from Him.

His heart is full of love; He grieves that we want to take

our own way, and go far-off from Him.

But if we are sorry, and come back to His loving arms,

we shall find that they will open to receive us; He will put
the best robe upon us, and He will prepare a feast for us;
and there shall be joy in the presence of the angels of God
over one sinner repenting!

Do you want to know what the "best robe" means?

 It is the Robe of Christ's righteousness. For Christ's
sake, who has shed His precious blood to make us clean
and white, we can be dressed in that perfect robe; and then
we shall be fit to join in the feast and the rejoicings, which
are coming by and by in heaven.

XXIX. The Pharisee and the Publican

Two men were wending their way towards God's Temple

at Jerusalem, a Pharisee and a Publican.

There, on a hill, stood the beautiful building with its

white marble pillars glistening in the sun; and as they
walked along the hot roads towards God's House, their
thoughts were very different.

They knew that God's Holy Presence was in that Temple

to which they were going, and one of them thought with
awe that he would soon be in the place where he would
meet with God.

The other man was thinking entirely about himself, and

nothing at all about God.

So they ascended the many steps leading up into the

Temple, and at last stood within the Sacred House.

* * * * *
 And then the Pharisee thought of how he understood all
about God's law, and how he did not need anyone to teach
him what was written in the Scriptures.

But he did not know two things which would have made
him a different man—he did not know his own heart, and he
did not know God's heart.

He did not know that his own heart was full of pride and
love of self; he did not know that God's heart was full of
pity and tender love towards sinful men who came to Him
to be forgiven.

So the Pharisee began to pray. And when the Lord Jesus

told us this story about him, He said "he stood and prayed
thus with himself."

But he began his prayer like this:—

"God! I thank thee that I am not like other men! I am

not one who exacts more than I should from others; I am
not unjust or impure; or even like this Publican. I fast twice
in every week, and I give tithes of everything I have."

Then the Pharisee, having finished his prayer, went

down once more to his home.

He had not seen the vision of God! He had not come

near to Him, nor waited to receive the answer to his words.
He did not even know what he had missed!

* * * * *

And the other man who went up to pray was the

Publican.
 He was a collector of the Roman taxes; and because of
the frequent cheating of these publicans, they were hated
by the Jews.

It was a calling which gave great opportunities for

dishonesty, and when some of the Jews, for the sake of
gain, engaged in it, they were despised and called traitors.

So this Publican, whom our Lord Jesus told about in this

story, was evidently a Jew, as he among other Jews "went
up into the Temple to pray."

And when he entered God's House, there stood the

Pharisee praying; but the Publican, standing afar off, not full
of his own good deeds, but feeling ashamed of his own
sinfulness, would not even lift up his eyes to Heaven, but
smote his breast saying:

"God be merciful to me, a sinner!"

* * * * *

And our Lord turned to those who were listening to Him

and said, "I tell you, this Publican went down to his house
justified, rather than the other."

Do you wonder what it is to be justified? Should we not

all like, when we have been naughty, or have done wrong,
to know that we may go down, like the Publican did to his
house, justified?

It means, I think, for a person to realise that some one

greater and richer than himself has undertaken to set him
free from his debt.
 It means that we have come to God and told Him that
we are very sorry we have been naughty, and have asked
Him to have mercy upon us, and to forgive us for Jesus'
sake.

When we have done that, we may, indeed, like the

Publican, go away "justified."

Perhaps some boy gets into trouble at school, and owes

something to another boy, which he has no means of
paying.

So the boy who owes the money goes to his father. He

knows he has done wrong, but he tells his father all about
it, and asks him to help him. And the loving father sees to it
all for him, and pays the debt.

The school-fellows know nothing about this, but they

have heard about the debt, and they whisper to each other,
and jeer when the boy comes near.

But to their surprise, he raises his head now! "My father

has paid," he says, with shining eyes.

I think that is being "justified."

* * * * *

And it seems to me that that was how the Publican felt,

when he had told God he was a sinner, and had asked for
His mercy.

He went home happy, and forgiven!

 GOD BE MERCIFUL TO ME, A SINNER!

Here is a comforting promise for us all—

"This is a faithful saying . . . that Christ Jesus came into

the world to save sinners!"
 XXX. An Uninvited Guest

One day the Lord Jesus was invited to dinner by a rich

man whose name was Simon.

Perhaps this rich man asked Jesus to dinner because he

wished to see Him do some miracle—something wonderful
which no one else could do; or he may have imagined that
people would think more of himself if he had Jesus for a
guest; at any rate, by what we read afterwards, I am afraid
Simon the Pharisee did not invite Jesus because he loved
Him.

But there was somebody present at that feast who did

love Jesus, but she was not invited.

In Eastern lands the houses are not shut up like our

houses, but because it is so warm, the dining-rooms are
often open to the air on one or two sides, or people take
their meals in the cool shady courtyards.

When a great man makes a feast, people hear of it, and

come round the house to look at what is going on.

In the city there lived a poor sinful and sorrowful

woman who had learned to love the Lord Jesus: perhaps
she had heard Him say these loving words, "Come unto Me,
all ye that labour and are heavy laden, and I will give you
rest."

When this sorrowful woman heard that Jesus was gone

to dinner at the Pharisee's house, she brought a little box
made of alabaster, which was filled with some very sweet-
smelling ointment, and she made her way into the open
dining-hall, and when she saw where the Lord was sitting or
reclining, as the custom was, on a sort of couch to the
table, she came up, and stood behind Him!

And as she stood there and thought of all His love and
compassion, she began to weep, and her tears fell down
over His feet as He reclined at the table.

Then she wiped His feet with her hair, and anointed
them with the sweet ointment.

But the Pharisee who had invited the Lord Jesus looked
on with anger. He thought if Jesus were a great teacher, He
would not have allowed a woman from the city to come and
wash His feet with her tears.

But Jesus knows all our hearts, and He could see that
the poor woman loved Him so much that she would go away
and try never to grieve Him any more.

By and by He turned to Simon, and told him to look at

this woman and compare her love with his.

Jesus said words something like this: "Simon, I was

tired and dusty with my journey when I came in, and you
did not give me water to bathe my feet, but she has washed
my feet with tears; you did not offer me a kiss, but this
woman has not ceased to kiss my feet; you did not anoint
my head with oil, but she has anointed my feet with
precious ointment. She has loved me very much, because I
have forgiven her very much."

And turning to the woman, Jesus said to her, "Thy sins

are forgiven; . . . go in peace."

Oh, the joy of hearing Jesus say those words!

 And we may have that joy too, if we come to Him with
humble loving heart, and tell Him that we are sorry.

He never turns anyone away who comes to Him; so,

dear little children, let us trust His loving heart, and though
we know we are very unworthy, do not let us stay away for
that, for Jesus longs that we may be forgiven, and so be
able to go away "in peace."

XXXI. The Barren Fig Tree

"Nothing but Leaves"

I have seen a picture of a fig tree, and I want to

describe it to you, that we may understand a little about
one of our Lord's Parables.

There are a great many Parables in the New Testament:

they are word-pictures to teach us God's great lessons.

At school your teacher has a large blackboard, and

sometimes she sketches an object, and explains it to you,
does she not?

One day she drew a cracked cup, the crack of which

grew wider under her clever fingers, and she turned round
and said to her class, "Is this cup of any use?" And there
were plenty of "No's" from all over the room; but one child
ventured "Perhaps it could be mended!"

And then the teacher gave a bright look, and she said,
"Yes, Charlie, you are right! And so are the others with their
'No's' all over the room. For unless the cup is mended, it is
of no use. The cup is a picture of our characters! If there is
a flaw in them, a crack that gets wider and wider, then the
cup is of no use, is it?"

"It might be thrown away!" ventured another child.

"Yes," said the teacher; "but, if it could be mended—as

Charlie said—then it could be used again. So what must we
do, Charlie?"

She turned her face to the little boy, and a smile came
over his features as he answered, "There's a china-mender
comes down our road every week—he could do it!"

And the teacher smiled back. Did Charlie know that he

had touched on a great truth? So she went on—

"Yes, we must 'have faith in God.' We must take our

cracked cups, and our faulty characters, to the Great
Mender, Jesus our Saviour, and ask Him to make us useful,
serviceable little Christians!"

So now, I am going to make an imaginary blackboard

and show you a branch of a fig tree!

Look at that fig growing out of the stalk; it is large, and

oblong, and plump, and it is firmly fixed to the big branch.

And then, above and below it are little sprouting leaves,

some just come out, some not yet burst from their little
buds; and soon the fruit, which is already ripe, will be
covered up by the leaves, as they grow larger and larger.

But suppose, when you lift the leaves, there is no fruit?

Then you come to the conclusion that the tree must be

a barren tree, and you turn away sorry and disappointed.

THE BARREN FIG TREE.

 And this is a little word-picture of the barren fig tree,
about which our Lord gives us a Parable.

He was coming from Bethany, and it says He hungered.

Perhaps the Lord Jesus had been up all night praying to His
Father.

So, as He came near to the fig tree, He saw it was full

of leaves; but when He got close to it, He found there were
no figs under the leaves—it was barren.

And as He turned away He said, in the disciples'

hearing, "Let no fruit grow on thee henceforward for ever."

Oh, how sad He was to have to say that!

And presently the fig tree withered away.

Just before this, the Lord came down the side of the
Mount of Olives, and in turning a corner of the steep path a
sight of the beautiful city of Jerusalem burst upon their
view. It says in the Gospel of Luke—

"And when He was come near, He beheld the city, and

wept over it, saying, If thou hadst known, even thou, at
least in this thy day, the things which belong unto thy
peace! But now they are hid from thine eyes."

Jesus wept for all the sorrow that was coming on the
beloved city, and because the Jews would not have Him as
their Saviour.

This was indeed like the fig tree, which had leaves, but
no fruit.

The Jews ought to have known from their own

Scriptures of the Old Testament, which they read every
Sabbath, that on this very day it was foretold in the Book of
Nehemiah, and also in Daniel and Zechariah, that the
Messiah was to enter Jerusalem as King, meek and lowly,
and riding on an ass's colt.

They were proud of their knowledge, and of their

possession of God's Temple, and His Scriptures; but they
had not fruit under the leaves of their pride and unbelief.
They had even been plotting to kill Him. They had rejected
Him in their hearts, and in a few days' time they were going
to crucify Him!

The next day Jesus and His disciples passed by that fig
tree again, and it had begun to wither and dry up; and the
disciples said, "How soon is the fig tree withered!"

And the answer of our Lord must have astonished them.

"Have faith in God!" He said.

Now, like the teacher with the blackboard, I want to

gather up the lesson I have learned from this story—

Do not let our dear Lord, Who died for us, come and
look into our hearts and find no fruit, but only leaves!

How He must long to have us all we should be!

Do not let us be like the cracked and useless cup! But

let us go to the great Healer and Mender and Cleanser of
our poor characters, and ask Him to make us what He
would like to see us.

The only way to get "mended" and to bear fruit instead

of only leaves, is to go to Him Who died on the Cross to
save us, and to find in Him forgiveness, strength, and
peace.
 XXXII. The Parable of the Talents

"What is a Talent?" perhaps some one asks.

A Talent in our Lord's time was a piece of money of

great value, of about £342, and in the story which Jesus
told the disciples, a Talent was described as something
precious which was given to the servants of a great lord, to
trade with, while he was on a long journey.

To one servant this lord gave ten Talents to trade with;

to another, five; to another, two; according to their several
ability; and to another, one.

And what do you think the servant who had only one
did with his Talent? He went away and digged in the earth,
and hid his lord's money!

Then the lord of those servants took his journey.

At length the time came for his return, and he called his
servants and reckoned with them.

The one who had traded with ten Talents brought ten
Talents more to his lord; and the man with five brought five
more; and the man with two brought two more. And the
lord was very pleased with these faithful servants, and said,
"Well done!" to each of them, and gave them great rewards.