Sarah J. Mass all 18 books: Assassin's Blade, Pirate Lord, Desert, Underworld, Empire, Healer, Court of Thorns and Roses, Silver Flames, Mist and Fury, Wings and Ruin, House of Earth Blood Sky and Air, Kingdom, Heir, Crown, Queen Tower, etc. Sarah J. Maas
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.
Contributors xi
Preface xv
Series editor biography xvii
Acknowledgment xix
Abbreviations xxi
1. Introduction on challenges for autoimmune diseases
Niloufar Yazdanpanah and Nima Rezaei
1 Introduction 1
2 Challenges in pathophysiology 2
3 Challenges in diagnosis 3
4 Challenges in treatment 4
5 Challenges in prevention 6
6 Conclusion 7 References 7
2. From horror autotoxicus to autoimmunity. An historical note
Domenico Ribatti and Enrico Crivellato
1 Introduction 10
2 Paul Ehrlich and the “horror autotoxicus” 10
3 First evidence 11
4 Autoimmunity in thyroid 11
5 Burnet and the prohibited clones 12
6 Further evidence 12
7 Influence of HLA complex 13
8 Vaccination and therapeutic approaches 14
9 Criteria of definition and classification of autoimmune diseases 14
10 Conclusion 14 References 15
3. Flow cytometry in the diagnosis of autoimmune-related lymphoproliferative disorder and lymphoma in the head and neck region
Lin (Jonathan) He, Franklin Fuda, and Mingyi Chen
1 Introduction 18
2 Representative histopathology, immunohistochemistry, and flow cytometry 22
3 Further discussion 30
4 Conclusion 33 References 33
4. Autoantigens in atopic dermatitis: The characterization of autoantigens and their diagnostic value
Marlon Múnera, Andres Sanchez, Emiro Buendía, and Jorge Sanchez
1 Introduction 37
2 Physiology of the skin 38
3 Clinical characteristics of dermatitis; treatment and classification 39
4 Molecular mimicry in atopic dermatitis (AD) 40
5 Tools for the study and identification of autoantigens in atopic dermatitis 43
6 Particularities of type 2 immune response in atopic dermatitis 44
7 Conclusion 45 References 45
5. Current paradigms of pathogenesis and challenges in vitiligo translational research
Shahnawaz D. Jadeja, Ankit H. Bharti, Mitesh Dwivedi, Jayvadan Vaishnav, Jay Mayatra, Ashwin Kotnis, Amina R. Gani, Naresh C. Laddha, and Rasheedunnisa Begum
1 Introduction 50
2 Understanding the pathogenesis of vitiligo 51
3 Histopathology of vitiligo 53
4 Current therapeutic modalities in vitiligo 55
5 Current translational research in vitiligo 61
6 Current challenges and future therapeutic avenues 65
7 Conclusion 66 References 67
6. The role of kynurenine pathway aryl hydrocarbon receptor axis in autoimmune diseases of the skin
Rowland Noakes
1 Introduction 79
2 The kynurenine pathway 80
3 The aryl hydrocarbon receptor 80
4 Autoimmune diseases 81
5 The immune response in the skin 82
6 Bullous pemphigoid 82
7 Systemic sclerosis 83
8 Vitiligo 84
9 Cutaneous disorders orchestrated by interferons 85
10 Frontal fibrosing alopecia 86
11 Conclusion 87 References 87
7. COVID-19 in childhood and phenotypes of pediatric inflammatory multisystem syndrome
Consolato M. Sergi
1 Introduction 91
2 COVID-19 92
3 Kawasaki disease 93
4 Kawasaki-like phenotype 94
5 PIMS spectrum 94
6 Coronary artery aneurysm 95
7 Future directions 96
8 Conclusion 97
References 98
8. Autoimmune conditions and epigenetic challenges in periodontitis
Farah Asa’ad, Carlos Garaicoa-Pazmiño, and Lena Larsson
1 Introduction 101
2 Role of autoimmunity in periodontitis 102
3 Role of epigenetics in susceptibility to periodontitis 105
4 Recommendations and future directions 111
5 Conclusion 114
References 114
9. Neutrophil extracellular traps in autoimmunity, renal diseases, and transplantation
Citlalin Vega-Roman, Zesergio Melo, and Raquel Echavarria
1 Introduction 122
2 Mechanisms and function of neutrophil extracellular traps 122
3 The role of NETs in autoimmunity 125
4 Clinical implications of neutrophil extracellular traps in renal diseases 127
5 NETosis from the bench to the bedside 130
6 Conclusion 132
References 132
10. Membranous nephropathy: Clinical and immunological aspects
Israel Nieto-Gañán, Claudia Geraldine Rita, Ignacio Iturrieta-Zuazo, and Ángela Carrasco-Sayalero
1 Introduction 139
2 Epidemiology 140
3 Clinical aspects 141
4 Immunopathogenesis 142
5 Diagnostics 152
6 Treatment 156
7 Conclusion 159
References 159
11. Testicular immune tolerance and viral infections
Sulagna Dutta, Pallav Sengupta, and Srikumar Chakravarthi
1 Introduction 170
2 Testicular immune privilege: Hide-out for virus 170
3 Anatomical basis of testicular immune privilege 172
4 Molecular basis of tolerogenic microenvironment in the testis 172
5 Common testicular viral infections 173
6 Testicular antiviral defense mechanism 175
7 Conclusion 177 References 177
12. Ophthalmological manifestations of systemic autoimmune diseases
Marija Barišic
Kutija
1 Introduction 183
2 Rheumatoid arthritis 184
3 Primary Sjögren’s syndrome 189
4 Seronegative spondyloarthropathies 192
5 Juvenile idiopathic arthritis 194
6 Systemic lupus erythematosus 198
7 Giant cell arteritis 203
8 Granulomatosis with polyangiitis 205
9 Multiple sclerosis, optic neuritis, and seropositive optic neuritis 205
10 Graves’ disease 208
11 Conclusion 211
References 211
13. Challenges for diagnosis and treatment of primary biliary cholangitis
Atsushi Tanaka
1 Introduction 215
2 Epidemiology 216
3 Etiology 218
4 Diagnosis 222
5 Treatment 226
6 Management of symptoms, extrahepatic manifestations, and hepatocellular carcinoma 231
7 Conclusion 234 References 235
14. Modeling primary biliary cholangitis and primary sclerosing cholangitis as infectious diseases
Kiandokht Bashiri, Stephen Ip, and Andrew L. Mason
1 Introduction 244
2 PBC 249
3 PSC 261
4 Conclusion 270 References 270
15. Humoral epitope spreading in autoimmune bullous diseases: An update
Dario Didona, Raffaele Dante Caposiena Caro, Luca Fania, Giovanni Paolino, and Biagio Didona
1 Introduction 288
2 Epitope spreading: Definition 288
3 Epitope spreading: Mechanisms 289
4 Epitope spreading in autoimmune bullous diseases 290
5 Conclusion 304
References 304
16. Dermatologic autoimmunity associated with immune checkpoint inhibitors
Yannick S. Elshot, Siebe G. Blok, Marcel W. Bekkenk, and Tiago R. Matos
1 Introduction 312
2 Immune checkpoint inhibitors 314
3 Autoimmunity 316
4 Conclusion 323 References 324
17. Insights and strategies to promote immune tolerance in allogeneic hematopoietic stem cell transplantation recipients
Govindarajan Thangavelu, Sara Bolivar-Wagers, Ethan G. Aguilar, Stephanie Y. Rhee, Brent H. Koehn, Keli L. Hippen, and Bruce R. Blazar
1 Introduction 330
2 Acute GVHD 330
3 Chronic GVHD 333
4 Tolerance 335
5 Tissue tolerance and reparative processes 346
6 Conclusion 347 References 347
18. The potential of cellular transplantation to harness autoimmunity and reverse clinical diabetes
Kevin Verhoeff and A.M. James Shapiro
1 Introduction 362
2 Islet cell transplant 368
3 Islet cell regeneration and immune reset 374
4 Novel approaches to immunosuppression 376
5 Conclusion 378 References 379 Index 387
Contributors
Ethan G. Aguilar Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, 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 Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
Marcel W. Bekkenk Department of Dermatology, Amsterdam UMC, University of Amsterdam, 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 Minnesota, 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
Ángela Carrasco-Sayalero Immunology Department, University Hospital Ramón y Cajal, Madrid, Spain
Srikumar Chakravarthi School of Medical Sciences, Bharath Institute of Higher Education 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 Dentistry, 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 Biotechnology, Faculty of Science, Uka Tarsadia University, Surat, Gujarat, India
Raquel Echavarria CONACyT-Western Biomedical Research Center, Mexican Institute of Social Security, Guadalajara, Jalisco, Mexico
Yannick S. Elshot Department of Dermatology, Amsterdam UMC, University of Amsterdam; Department of Dermatology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Luca Fania Department of Dermatology, IDIIRCCS, Rome, Italy
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 Periodontics, University of Iowa College of Dentistry, Iowa City, IA, United States; School of Dentistry, Espiritu Santo University, Samborondon, 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 Minnesota, Minneapolis, MN, United States
Stephen Ip Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada
Ignacio Iturrieta-Zuazo Immunology Department, University Hospital Ramón y Cajal, Madrid, Spain
Shahnawaz D. Jadeja Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
A.M. James Shapiro Department of Surgery and Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
Brent H. Koehn Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
Ashwin Kotnis Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
Marija Barišić Kutija Department of Ophthalmology, 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 Dermatology, 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 Immunodeficiencies, Children’s Medical Center; Department 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
Stephanie Y. Rhee Division of Blood and Marrow Transplantation, Department of Pediatrics, 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 Department, University Hospital Ramón y Cajal, Madrid, Spain
Andres Sanchez Medical Research Group (GINUMED), Universitary Corporation
Rafael Nuñez, Cartagena; Group of Clinical and Experimental Allergy (GACE), IPS Universitaria, University of Antioquia, Medellín, Colombia
Jorge Sanchez Group of Clinical and Experimental 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, Children’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
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 Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India
Citlalin Vega-Roman Physiology Department, CUCS, The University of Guadalajara; Surgical 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 remarkable 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 enlightened different aspects of its complexity that lead to promoting diagnostic strategies, designing more efficient therapeutic agents, and reducing potential morbidities and mortality. Due to the broad spectrum of immunemediated diseases, from immunodeficiency to hypersensitivity and autoimmune diseases, the immune system diseases collectively contribute to a considerable prevalence, although every single immune-mediated disease represents a low prevalence.
The responsibility of applying the latest research findings had long been a concern for scientists. Translational research is recognized as a potential tool to utilize scientific findings in clinical settings and patients’ care. Considering the wide spectrum
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 translational studies is of interest.
The Translational Immunology book series is a major new suite of books in immunology, which cover both basic and clinical immunology. 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 specifically devoted to autoimmune diseases.
Translational Autoimmunity: Challenges for Autoimmune Disease explores the existing challenges in the pathophysiology, diagnosis, treatment, prognosis, and prevention of autoimmune diseases. Challenges in each of these aspects potentially challenge the others, highlighting the importance of translational studies on autoimmune diseases. For instance, challenges in identifying the details of the pathophysiology of autoimmune diseases, including the genetic background and the triggering factors, affect the development of diagnostic tools and treatments. Meanwhile, the prognosis of patients is affected since it is linked to the administered treatments. Taken together, detecting challenges in the field of autoimmune diseases and designing strategies to tackle them could have a remarkable effect on the patients’ quality of life, quality of the disease management, and the overall burden of the disease.
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 preparing 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 comprehensible, cogent, and of special value to researchers and clinicians who wish to extend their knowledge in immunology.
Nima Rezaei
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 autoimmune diseases and the challenges in the identification of these conditions. Chapters 3 and 4 dive deep into the challenges in the application of some of the diagnostic tools of autoimmune 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 autoimmune diseases. Chapter 7 emphasizes the possibility of autoimmunity following newly emerged diseases, by discussing the pediatric inflammatory multisystem syndrome following COVID-19, which raised concerns for pediatric health since the start of the pandemic. 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 autoimmune diseases.
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 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 projects and has designed and participated in several international collaborative projects. Professor Rezaei is an editorial assistant and board member for more than 30 international journals. He has edited more than 30 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1000 scientific papers in international journals.
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.
RANKL receptor activator of nuclear factor kappa B ligand
RBP retinol-binding protein.
RF rheumatoid factor
rhASB recombinant arylsulfatase B
rhGAA recombinant Human alpha-glucosidase
RLRs retinoic acid-inducible gene I (RIG-I)like receptors
RNFL retinal nerve fiber layer
ROS reactive oxygen species
RR relative risk ratio
RTX Rituximab
SAMHD1 sterile-α-motif and HD domaincontaining protein 1
SARS-CoV severe acute respiratory syndrome coronavirus
SCARs severe cutaneous adverse reactions
scfa short chain fatty acids
SCID severe combined immune deficiency
SCORAD severity scoring atopic dermatitis
SE shared epitope
SHM somatic hypermutation
SIB Swiss Institute of Bioinformatics
SLE systemic lupus erythematosus
SLL small lymphocytic lymphoma
SM Smith antigen
SMN secondary membranous nephropathy
SNP single-nucleotide polymorphism
SpA spondyloarthropathy
SR steroid refractory
SS Sjögren’s syndrome
STAT signal transducer and activator of transcription proteins
T1DM type 1 diabetes mellitus
TAO thyroid-associated ophthalmopathy
TCD T-cell depletions
TCDD tetrachlorodibenzoparadioxin
Tcons T conventional
TCR T-cell receptor
Teffs T effectors
TEN Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis
TEWL transepidermal water loss
TF tissue factor
Tfh T follicular helper cells
TGF transforming growth factor
Th T helper cells
THSD7A thrombospondin type-1 domaincontaining 7A
Tim-3 T-cell immunoglobulin mucin-3
TIMPs tissue inhibitors of MMPs
TJ tight junctions
TLR toll-like receptors
TMPRSS2 transmembrane protease serine 2
TNF tumor necrosis factor
Tr1 T regulatory type 1
TR1 Type 1 regulatory T cells
TRAIL TNF-related apoptosis-inducing ligand
Treg regulatory T-cells
TRP tyrosinase-related protein
TSLP thymic stromal lymphopoietin
tTG tissue transglutaminase
tTreg thymus regulatory T cell
tTregs thymic derived Tregs
UCB umbilical cord blood
UDCA ursodeoxycholic acid
UPR unfolded protein response
VEGF vascular endothelial growth factor
VISTA V-domain Ig suppressor of T-cell activation
XAP2 hepatitis B virus X–associated protein 2
XRE xenobiotic response elements
α-GalCer alpha-galactosylceramide
α-MSH alpha melanocyte stimulating hormone
1 Introduction on challenges for autoimmune diseases
Niloufar Yazdanpanaha,b,d and Nima Rezaeib,c,d,⁎
aSchool 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 tackled 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.
Autoimmune diseases are known as the consequence of the immune system’s misrecognition of self-antigens as harmful. About 5%–8% of the world population suffers from autoimmune 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 questions about autoimmune diseases remained to be addressed.
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 manifestations. 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 administered 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 underpinned the importance of multiomics research in the context of autoimmune diseases.
Treatment of autoimmune diseases has been always challenged by associated comorbidities 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 autoimmunity. 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 always 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
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 concurrence 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 arthritis (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 polyglandular syndrome (APS) [6]. This definition consists of both complete MAS and incomplete MAS, of which incomplete subtypes are more common. For instance, detection of autoantibodies 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 connective 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 management, 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
the evaluation becomes positive for a marker that predicts a high risk of developing autoimmunity, 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, ribonomics, and metabolomics research could be helpful in the recognition of new autoantigens, autoantibodies, and biomarkers for autoimmune diseases [11]. Finding specific markers for autoimmune 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 corticosteroids, 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 autoimmunity, 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 autoimmune 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 inflammation 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 candidates for autoimmune diseases. DMARDs consist of three main groups: conventional (csDMARDs), 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 monoclonal 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
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 malignancies [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, immune 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 repurposing 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 autoimmunity (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
