Translational Autoimmunity, Volume 1: Etiology of Autoimmune Diseases
By Nima Rezaei and Niloufar Yazdanpanah
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About this ebook
Translational Autoimmunity: Etiology of Autoimmune Diseases is the first volume of the Translational Immunology book series. To attain its purpose as a detailed translational step to tackle autoimmunity, this volume sufficiently addresses basic questions on how the immune system is designed to distinguish self from nonself. It discusses the known mechanisms that lead to the maintenance of self-tolerance, presents potential triggers and malfunctions that impede normal immune processes, and demonstrates how the immune system induces an autoreactive state that results in the recognition of self-antigens seen in autoimmune conditions.
- Includes coverage of basic immunology, the clinical aspects of autoimmunity, and translational immunology studies in autoimmunity
- Presents key concepts supported by a systematic appraisal of the most recent evidence
- Assists students at all the academic levels while also being applicable to scientists who work with autoimmunity
- Designed for learning, teaching, review, testing, practice and research
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Translational Autoimmunity, Volume 1 - Nima Rezaei
Chapter 1: Introduction on translational autoimmunity: From bench to bedside
Nima Rezaeia,b,c,⁎; Niloufar Yazdanpanaha,c a Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
b Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
c Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
⁎ Corresponding author
Abstract
The immune system is a potent complex system playing a crucial role in human existence. Immune-based diseases vary from an inborn defect in the immune system, which results in primary immunodeficiency, to an overactivation of the immune system, which turns into hypersensitivity states or malfunctions of the immune system in selfdiscrimination and nonselfdiscrimination, which ends in autoimmune diseases. In this chapter, autoimmune diseases are discussed from different points of view with a translational approach. Recent advances and discoveries in the field of immunology thoroughly highlight the significance of translational studies to apply the data from scientific investigations to clinical settings and patient care. Considering the huge burden of autoimmune diseases on patients, families, health care system, and society, applying translational research to optimize the current diagnostic tools and therapeutic strategies or to find out promising alternatives is of interest.
Keywords
Autoimmune disease; Autoimmunity; Immunodeficiency; Immunology; Translational
1: Introduction
Widespread in different tissues, in close contact with various cells, and with meticulous connections between its different components, the immune system is playing a crucial role in human survival since the first moment of life. The immune system consists of specific types of cells, and each is required to have close, special contact with the body’s various cells and tissues besides precise correlation with other immune cells to reach the optimal functional efficacy that is considerably higher than the sum of their individual functions. Cytokines and chemokines, soluble immune factors, are produced and released by immune cells to conduct signals and induce the required coordination and synchronicity. Furthermore, to recognize target cells or tissues, immune cells benefit from a wide variety of receptors, adhesion molecules, and surface markers. For instance, human leucocyte antigens (HLAs) are a prominent component of this widely extended network that help immune cells with recognition and discrimination of self and nonself to initiate further responses. The immunology-based sciences have developed exponentially in the last decades. Recent advances in controlling hypersensitivity and allergies, fighting against malignancies with the emergence of novel immunotherapy methods, approval of immune-based drugs and targeted therapies, development of genome-wide association studies (GWASs), and discovery ofcontributing genes to immune-related disorders all have been originated from advances in immunological studies. Considering recent developments in immunology, different pieces of the immune system puzzle are assembling and being put together to complete the complex schemaindicating how various parts of the immune system contribute to preserving human health. Besides all the aforementioned advances, our understanding of the total architecture of the immune system has undergone major changes. While the immune components have been categorized into two main groups, named innate and adaptive immune systems, during recent decades as our understanding of immune system interactions and interconnections in the human body increased, the immune system is now introduced as an integration of cross-talks between immune and nonimmune components such as commensal microorganisms [1] and nervous and endocrine systems [2–4]. Since the number of novel discoveries and developments in the field of immunology is growing at an unprecedented pace, the concept of translational immunology
has drawn a significant attention, and the importance of bench-to-bedside studies have been highlighted. Translational research focuses on the application of laboratory findings in the clinical setting and patient care.
Immune-mediated disorders include a vast spectrum of diseases with different clinical, histological, pathological, molecular, and laboratory manifestations. Infections, inflammatory disorders, immunodeficiency conditions, autoimmune disorders, hypersensitivity, and allergies are considered as the main categories of immune-mediated disorders. Moreover, the role of the immune system in transplant rejection, cancer formation and progression, metabolic disorders, inflammaging conditions, and neurodegenerative diseases is prominent enough to restrain the limited categorization and extend the scope of immune-related disorders. The following sections of this chapter is spotlighted on autoimmunity as an immense field of immunology with numerous interconnections and overlaps with other immune-related conditions.
2: Autoimmune disorders
First described with the term horror autotoxicus
in 1901 by Paul Ehlrich, German bacteriologist and immunologist, the scientific world faced a new sophisticated immune-related condition [5]. Autoimmune diseases are a heterogeneous group of diseases, in which the immune system lost its tolerance to self-antigens and fails to distinguish between self and nonself. Considering the data from the most recent comprehensive studies on the incidence of autoimmune disorders, an annual incidence rate of 1.3 new cases per 1000 female individuals and 0.5 new cases per 1000 male individuals has been estimated for the United States (US) in 1996 [6]. These investigators have reported a prevalence rate of 3.2% of the US population (about 9 million individuals) to have at least one autoimmune condition [6]. In 2005, the National Institute of Health has reported that 14.7 to 23.5 million individuals in the US suffer from at least one autoimmune disease [7]. Regardless of the low prevalence of every single autoimmune disease, it has been reported that autoimmune conditions are detectable in 3%–5% of the overall population [8]. According to the Autoimmune Registry, the most common autoimmune disorders are rheumatoid arthritis (RA), Hashimoto’s autoimmune thyroiditis, celiac disease, Graves’s disease, and type 1 diabetes mellitus (T1DM), respectively [9]. Since complete relief and cure of most of the autoimmune conditions has not been achieved so far, it put a significant burden on patients, society, and the health care system. Individuals face different disabilities followed by reduced productivity at work, which besides huge medical expenses potentially imparts an extra burden of patients’ life and the society. On the other hand, the mental burden of being chronically sick and further emotional discomfort might be an important challenge in these patients’ life.
3: Pathogenesis and mechanisms of autoimmune diseases
Recognition of self from nonself is instrumental for the proper function of the immune system. The programming of immune cells to not inducing immune responses against self-antigens is named immunological tolerance
, which consists of two main parts, central tolerance and peripheral tolerance, which take place in central lymphoid organs, such as thymus and bone marrow, and in secondary lymphoid organs, such as spleen, mucosal lymphoid tissue, and lymph nodes, respectively. Central B cell tolerance particularly occurs in the bone marrow by two main mechanisms named as receptor editing and apoptotic cell death [10, 11], whereas the central tolerance mechanisms for T cells are not completely documented and require further investigations. Despite the undetermined central tolerance system of T cells, great efforts have been made that have resulted in the inauguration of immune ignorance, positive selection, and negative selection as the main mechanisms of T cells’ central tolerance [12, 13]. The first step is performed with the contribution of thymic cortex cells that present the MHC-peptide complex to T cells aiming to detect the ones that are not sensitive to the MHC-peptide complex [14]. T cells that pass through this step are double positive (CD4 + CD8 +) T cells that transfer to the medullary regions of the thymus and undergo the negative selection process, which potentially delete the cells with high affinity to selfantigens, to become single positive cells (CD4 + or CD8 +) [15]. It is of high value to mention that the discovery of promiscuous gene expression was a milestone in immunology as it rationalized the amazing capability of medullary epithelial cells of the thymus in expressing and presenting a wide variety of self-tissue antigens to develop T cells maturation [16]. Promiscuous gene expression is regulated by autoimmune regulator (AIRE) gene that is exclusively expressed in thymic medullary epithelial cells [17, 18]. AIRE mutation has been claimed to be related with different autoimmune diseases. Besides the central tolerance, the peripheral tolerance contributes to the maintenance of the tolerance to self by detecting the escaped autoreactive cells as well. Peripheral tolerance for B cells is conducted in two pathways; the first is when the B cell becomes exposed to the antigen in the absence of the proper T helper cells (Th), which ends with the deactivation of the B cell. The second pathway is follicular exclusion, which is when the B cell become partially activated and fails to conduct a complete response and is excluded from the lymphoid follicles [19]. Regarding T cells, anergy, deletion, and immune suppression are counted as known mechanisms of peripheral tolerance. Clonal anergy occurs in exposures of T cells with antigens that are provided by either a non-APC (antigen presenting cell) or an inappropriate APC. A non-APC does not provide the T cell with costimulatory molecules that are essential besides the MHC-peptide complex for a proper T cell activation and initiation of the immune response. However, in the other condition, it might be possible that the APC provides both MHC-peptide complex and costimulatory molecule, but the latter is of the inhibitory type (CLTA-4 instead of CD28) [20, 21]. Deletion mechanism is due to the expression of Fas (CD95), and FasL (CD98L) results in activation induced cell death, which occurs in cases of inappropriate activation of T cells or hyperactivation in antigen overloads [22]. The last-mentioned mechanism, immune suppression, is related to the effect of T regulatory (Treg) cells in modifying T cell responses that benefit the maintenance of self-tolerance [23]. Thus, any impairments, dysregulation, and inadequate activity in these pathways may result in a break of tolerance and initiate the autoimmune process.
4: Predisposing factors
Autoimmune diseases are multifactorial disorders, and individuals from different races, genders, and with various genetic and environmental predisposing factors are observed to be prone to different autoimmune diseases with a wide spectrum of the severity of condition. As an illustration, systemic lupus erythematosus (SLE) and systemic sclerosis have been observed to have higher prevalence rates, start at lower ages, and represented a more severe from of the disease in African Americans compared to European Americans [7]. Nevertheless, African Americans are less prone to thyroiditis, multiple sclerosis (MS), and T1DM [7]. To highlight the effect of gender in susceptibility to autoimmune diseases, it has been reported that about 65% of the autoimmune patients are female. Hence, the majority of autoimmune diseases have shown a tendency to affect women with the exception of small-vessel vasculitis and T1DM [24].
Autoimmune diseases are correlated with a wide variety of risk factors. RA, the most prevalent autoimmune disease, is associated with environmental, habitual, and nutritional factors. It is well-documented through several studies that smoking has a prominent association with RA incidence in individuals with HLA-DRB1 gene epitope and probably with accelerated joint destruction besides the severity of the disease phenotype [25–27]. It is worth mentioning that smoking increases the risk of RA either directly, by inducing oxidative stress, provoking the release of autoantibodies, initiating inflammation, and apoptosis, or indirectly, by prompting epigenetic changes [28]. Diet and nutritional habits have proven interconnections with autoimmune diseases by influencing epigenetics and affecting immune cells’ reprogramming through immunometabolism processes [29–31]. A large proportion of omega-6 fatty acids intake might incline the immune system to a pro-inflammatory state that, in turn, increases the risk of autoinflammatory diseases, while omega-3 fatty acids consumption reverses this process by inducing antiinflammatory effects [32, 33]. Excess minerals intake also influences the susceptibility to autoimmune diseases such as RA. For instance, high levels of sodium affect the immune system in several aspects, including suppression of Treg cell function, pro-inflammatory cytokines, and reactive oxygen species (ROS) production, which leads to inflammasome formation, and disturbance of the innate-adaptive immune imbalance [34–36]. Putting all these together, sodium overload potentially predisposes individuals to autoimmune responses. Nevertheless, caffeine has been introduced as an immunomodulatory agent since its suppressive effect on macrophages, natural killer (NK) cells, and some inflammatory cytokines were observed through several studies [37, 38]. Moreover, a decline in Th1 responses and balance in Th1/Th2 production has been reported as a result of physical activity [39]. Hence, physical activity is recapitulated as an immunomodulatory mechanism that might benefit autoimmune patients. Obesity, as a growing global dilemma, has been known to have an association with a broad spectrum of diseases. Indeed, due to the chronic inflammatory state that is observed in obese individuals, obesity is counted as a risk factor for metabolic, autoimmune, and degenerative diseases [40]. Furthermore, the discovery of adipokines, which are immune secretions of the fat tissue, has strengthened the association of obesity with autoimmune diseases [40]. Concerning reports on the possibility of obesity transfer in microbiome transplantation investigations, it has been proposed that the microbiome might be the missing link between nutritional habits, obesity, and autoimmune diseases [31, 41]. It is also worth mentioning that these risk factors might impact individuals’ response to treatment besides their effect on the predisposition of patients to autoimmune diseases. For instance, obese patients have represented a lower response to tumor necrosis factor (TNF) inhibitors [30]. Therefore, the importance of different phenotypes of the disease and recognition of various risk factors to select the best therapeutic method is undeniable.
5: Role of genetics
It is widely accepted to presume a genetic susceptibility for autoimmunity that is triggered or flared by different factors. For instance, infections can initiate autoimmunity by molecular mimicry, B cell polyclonal activation, propagation of sequestered antigens in immune-privileged tissues, uncontrolled expression of MHC II in different tissues, and the aging process of the thymus. Additionally, noninfectious factors, such as estrogen, changes in the normal body homeostasis, and exposure to an external environmental trigger, which in most cases the trigger is not determined, and a number of the drugs potentially induce autoimmunity [42]. Furthermore, last decades have witnessed profound growth in the body of research about the interconnection and concordance of autoimmunity with immunodeficiency, and now immunodeficiency can be considered a contributing etiology to ignite autoimmunity. A report from the French national primary immunodeficiency registry (CEREDIH) in 2017 revealed that 26.2% of patients with primary immunodeficiency diseases (PIDs) experience one or more autoimmune conditions during their life, and the incidence of autoimmunity is of prognostic value in these PID patients [43]. Additionally, they have estimated the risk of autoimmune cytopenia to be 120 times higher in PID patients compared to other patients [43]. As an illustration of the association between immunodeficiency and autoimmunity, immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome is due to a mutation in the FOXP3 gene, which in turn causes impaired function of the T regulatory cells and, hence, a favorable condition for autoimmunity prepared [44]; the other example could be the Wiskott-Aldrich syndrome, which is reported with high levels of autoantibodies that predispose the patient to autoimmune diseases [45]. Overall, PIDs with defects in T regulatory cells (IPEX, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and Omenn syndrome) have been demonstrated to occur in association with autoimmunity with a penetrance of 100% [45]. Although the interconnection between autoimmunity and PIDs with B cell defects are observed less frequent than the interconnection with T cell defects, reports regarding the accompaniment of autoimmune cytopenia with autoimmune lymphoproliferative syndrome (ALPS) points to the possible role of B cells in inducing tolerance to the blood cells [45]. Moreover, the association between autoimmunity and hypersensitivity is a significant issue to be addressed. As per available research, allergic reactions may occur, even in the absence of exogenous allergen, and it has been observed that the pattern of reactions is Th1-mediated (that is provoked by IgE-reactive autoantigens), which is the hallmark of type 4 hypersensitivity rather than type 1, which is IgE mediated [46]. Thus, the activation of Th1-mediated responses might potentially link hypersensitivity and allergy to autoimmunity.
Taken together, these findings demonstrated that autoimmunity is tightly connected to other immune-mediated conditions, both immunodeficiency and hypersensitivity. This highlights the significance of an integrated comprehensive approach to better understand the concept of autoimmunity. Discovering novel genes and mutations that are involved in autoimmune disease are all possible by focusing on the interconnections between different kinds of immune-mediated diseases. Furthermore, application of these findings in clinical settings, known as translational research, will be more accessible through this integrated approach. For instance, as mentioned before, genetic studies of PID patients have revealed genes that were also involved in autoimmunity, while these findings were in line with the patient’s clinical manifestations. Considering the current evidence, physicians might be aware of the probable risk of infection-related issues in autoimmune patients with disease-modifying antirheumatic drugs (DMARDs) treatment to be able to control these issues.
6: Obstacles in treatment
Besides different side effects, current approved therapeutic agents for autoimmune diseases are not specifically designed for a certain condition and have a broad-spectrum effect. Janus kinase (JAK) inhibitors are now the most popular therapeutic agent in clinical settings [47]. This drug family has obtained approved indications in RA, psoriasis, alopecia areata, and inflammatory bowel disease (IBD). However, due to the low specificity for their targets, JAK inhibitors have demonstrated annoying side effects such as various types of bacterial, viral, and fungal infections [31]. Other therapeutic options for autoimmune diseases include TNF inhibitors, inhibitors of different interleukins and costimulatory molecules, monoclonal antibodies targeting integrins and B cells, and cell therapy methods. However, there are several reports of further complications in individuals who have been treated with biological agents. A Spanish study has demonstrated that treatment with biological agents might potentially induce autoimmune diseases in patients [48]. Psoriasis, IBD, central nervous system demyelinating diseases, interstitial lung disease, and SLE were the most common induced autoimmune diseases according to this study that have mostly appeared in patients with rheumatic diseases, cancers, and IBD [48]. GWASs are promising tools in identifying the responsible genes for causing different responses to treatments besides discovery of novel genes that contribute to the etiopathogenesis of autoimmune diseases [31, 49]. Demyelination and multiple sclerosis-like symptoms were reported as side effects of TNF inhibitors since the start of the clinical application of these drugs. However, GWASs have discovered a genetic variation in the TNF receptor gene that prone the TNF inhibitor-consuming patients to MS [50]. Consequently, this finding has restrained the administration of TNF inhibitors for these patients. Additionally, there are alternative therapeutic methods that have represented promising results. For instance, methods targeting metabolic pathways in immune cells, microbiome manipulation, and utilization of novel genome editing techniques such as chimeric antigen receptor (CAR) T cells and CRISPR-Cas 9 technology [31, 51–53]. Nevertheless, consideration of the further probable complications in designing and utilizing alternative methods is of high value as the human’s complex immune system and its interactions with different nonimmune systems have still unknown features. To illustrate, novel therapeutic compounds targeting immune checkpoint molecules might increase the risk of tumor development and infection [54].
The process of getting approval for a novel therapeutic agent has long been associated with numerous challenges that only about 10%–15% of drug candidates, which enter phase 1 clinical trials, will get the final approval; except from recombinant proteins, which might have an estimated higher chance of approval [55–57]. It implies that the process of passing preclinical studies to entering phase 2 and 3 clinical studies is extremely time-consuming and expensive [58]. Therefore, translational studies might help accelerating this process by identifying certain involved pathways and mechanisms in the physiopathology of autoimmune diseases to specifically targeting these pathways.
7: Diagnostic tools
The heterogeneity in manifestations and disease progress in autoimmune disorders highlights the importance of defining appropriate biomarkers for disease diagnosis prior to the emergence of symptoms, as well as monitoring, and determining the prognosis of patients. With respect to the previous studies, three main groups of proteins are targeted in biomarker investigations: (1) immune system-related mediators, such as cytokines and growth factors; (2) degradation products that are the results from tissue injury; and (3) enzymes that are engaged in inducing tissue injuries [59]. For instance, antinuclear antibody (ANA), anti-dsDNA antibody, anti-Sm antibody, and anticardiolipin antibody (aCL) for SLE [60] and anti β2-glycoprotein 1 and aCL for antiphospholipid syndrome [61] are among the most common biomarkers detected in laboratories. Furthermore, anti-dsDNA autoantibody and antineutrophil cytoplasmic autoantibodies (ANCA) are prognostic biomarkers that might determine the severity of the disease and the probability of flares in SLE and ANCA-associated autoimmune vasculitis (as in Wegner’s granulomatosis), respectively [62–64]. Indeed, while the mentioned markers are helpful in the diagnosis of autoimmune diseases, the interpretation of these test results, ANA in particular, must be based on an individual’s characteristics and the clinical status of the patient since they can be detected in healthy individuals or patients with cancer, some cases of chronic infections, and as an adverse effect of particular medications [65]. Moreover, there are alternative promising new strategies for detecting newer and more efficient biomarkers. Serum microRNA profiling, evaluating proteomic biomarkers, and detecting the altered epigenetic changes, are of those new strategies that require further research [66–68].
8: Role of innate immunity
Although adaptive immunity has been known to be responsible for inducing autoimmune conditions from the very first investigations, now the contribution of innate immunity to conducting autoimmune responses is being revealed and accepted by the scientific community. Considering the various components of innate immunity including NK cells, dendritic cells (DCs), neutrophils, macrophages, complement system, inflammasomes, and different receptors, including Toll-like receptors (TLR), investigating novel innate immunity’s pathways involved in autoimmune responses is of interest. For instance, activation of the innate immune system by recognizing some constituent of the immune complexes by the means of both TLR and non-TLR receptors results in the production and release of IFN-γ that, in turn, leads to naïve T cell development and exacerbation of autoimmune responses [69, 70]. Supporting this notion, there are recent records on the abnormal activation and function of TLR7, TLR6, and TLR9 in several autoimmune patients [71, 72]. Besides, NK cells have been observed to have the ability to invade autoreactive cells as their role in omitting cancerous cells and infected cells [73]. Hence, the role of NK cells in autoimmunity might be the prevention of autoreactive cell induction either by producing cytokines to inactivate T cells and B cells or by restraining the DCs in presenting self-antigens to effector cells [74, 75]. However, several reports have demonstrated that the number of NK cells decline in patients with autoimmune diseases besides the change in their function or phenotype [70, 76–78]. The most abundant type of leukocytes in humans, neutrophils [79], are potentially involved in autoimmune processes as well. It has been documented that neutrophils extracted from an autoimmune patient’s blood have a greater tendency to undergo NETosis (NET: neutrophil extracellular trap) [80]. Since most of the externalized molecules by NETosis are potentially considered autoantigens, the role of neutrophils in autoimmune responses is implied [80]. Integrating all the mentioned data, the prominent effect of innate immunity, as a main arm of the immune system, in inducing and maintaining autoimmune responses is discernible. Therefore, investigating either the innate or adaptive immune systems might lead to the recognition of new pathways and provide novel insights to design new therapeutic agents and diagnostic tools for autoimmune diseases.
9: Conclusion
Regardless of the recent boost in the knowledge of autoimmunity, most of the scientific findings are in the field of etiology and pathophysiology of autoimmune diseases while the utilization of these findings in designing appropriate treatments does not meet the patient’s needs. Therefore, the scientific world is required to translate the discoveries about the pathological and physiopathological mechanisms to therapeutic methods and novel drugs. However, many challenges exist in translational studies. Since most of the newly obtained data is rooted in animal studies, it might not be completely extrapolative to the human system [58]. In other words, the lack of direct data from human autoimmune molecular phenotype is one major obstacle in translational research [58]. It is noteworthy that in all fields of medicine, prevention should be prior to treatment. In line with this widely accepted notion, in the field of autoimmune diseases, prevention by controlling risk factors and postponing either the onset or progression to severe course of the diseases by early interventions is of interest. Furthermore, due to the defect in the immune system of autoimmune patients, they are more vulnerable to develope other autoimmune disorders [81]. Therefore, investigating the shared pathways in different autoimmune diseases and responsible genes in the pathogenesis of autoimmunity will remarkably benefit these patients. One more challenge in the treatment of autoimmune diseases might be the effect of the circadian rhythm of the immune system. Circadian rhythm in the immune system interprets the activity period of each type of immune cell and the surges and fall in the concentration of the immune system’s secretions, such as cytokines [82]. It implies that the time of drug administration should be determined based on the target of the drug in autoimmune diseases to reach the optimal efficacy. To draw a conclusion upon these evidence, optimizing the diagnostic tools and treatment strategies is achievable through a better understanding of the underlying mechanisms and genetics behind autoimmunity. Translational studies are necessary to prepare the obtained data from preclinical and laboratory studies for application in clinical