Translational Autoimmunity, Volume 3: Autoimmune Disease Associated with Different Clinical Features

By Nima Rezaei

Translational Autoimmunity: Autoimmune Diseases in Different Clinical Settings addresses autoimmunity and associated conditions, such as aging, infectious diseases, cancer, neurodegeneration, psychological disorders, fertility, inflammatory vascular diseases, and interstitial lung diseases. The book addresses sufficiently basic questions on how the immune system is designed to distinguish self from no self and behave such that it's able to maintain self-tolerance, how does it work in infections, and how it elicits an auto-reactive state and develops self-antigens seen in autoimmune conditions.

This is followed by an overview on the genetic and clinical aspects of the spectrum of autoimmune diseases which are broadly categorized into two types of organ specific autoimmune diseases and non-organ specific autoimmune diseases (also known as systemic autoimmune diseases).

• Covers clinical aspects of autoimmunity and translational immunology studies in autoimmunity in different clinical settings
• Meets the needs of basic scientists, clinicians, translational scientists and industry partners
• Supported by a systematic appraisal of the most recent evidence

• Language: English
• Publisher: Academic Press
• Release date: Apr 1, 2022
• ISBN: 9780323854160

Book preview

Chapter 1: Introduction on autoimmunity and associated conditions

Nima Rezaeia,b,d,*; Niloufar Yazdanpanaha,c,d    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 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

d Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

⁎ Corresponding author

Abstract

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

Keywords

Autoimmunity; Immunodeficiency; Cancer; Metabolic diseases; Infection

1: Introduction

Autoimmune diseases are associated with a broad spectrum of medical conditions, which could be attributed to the multifactorial and unknown etiology of autoimmune diseases. Autoimmune diseases emerge at different ages, from the very first days of life to the elderly. Autoimmune manifestations have been reported in genetic syndromes and inborn errors of immunity (IEI), which are chiefly diagnosed in the early years of life. Although advances in diagnostic methods have facilitated and accelerated the diagnosis at earlier stages of the disease, and novel therapeutic strategies have successfully reduced the complications of the disease, the associated autoimmune manifestations could persist even after receiving proper treatment. Therefore, it imposes a remarkable burden on individuals, families, health-care services, and society.

There is a mutual association between malignancy and autoimmunity. The paraneoplastic syndrome is known as an accompanying condition to malignancies, which occurs following abnormal anticancer immune responses that target the normal tissues of the body. On the other hand, the risk of some specific types of malignancies is potentially higher in patients with autoimmune diseases. The latter could be attributed either to the overall inflammatory state, which is dominant in autoimmune patients, or to the immunosuppressive/immunomodulatory effects of medications prescribed for autoimmune diseases.

In addition, infections have been long known as one of the most important triggering factors of autoimmunity. Since infections, opportunistic infections in particular, are reported as an adverse effect of autoimmune treatments, a bidirectional association could be hypothesized in this context as well.

Besides all the above-mentioned associations, autoimmune diseases could be associated with comorbidities that affect patients’ quality of life (QoL). For instance, obesity, infertility, stress and mental complications are some of the main factors influencing patients’ QoL. Hence, highlighting the associations and comorbidities of autoimmune diseases might lead to better management of patients and potentially attenuate the severity of associated conditions. This chapter aimed to provide a comprehensive overview of the current literature on autoimmunity and associated conditions.

2: Autoimmunity and infection

Classically, it was widely accepted that infections trigger autoimmunity and rheumatic fever has been recognized as the most well-known example of conditions that is triggered by infectious agents (group A beta-hemolytic streptococcus) [1]. Several mechanisms have been proposed to explain infection-induced autoimmunity, which are dependent on the breakdown of tolerance, such as molecular mimicry, polyclonal activation, epitope spreading, and bystander activation [2]. However, the role of infections on autoimmune diseases has extended from a triggering factor to an inhibiting factor. For instance, inflammatory bowel disease (IBD) is reported to be attenuated in patients with helicobacter pylori infection [3, 4]. Hygiene hypothesis, which was initially stated by Strachan in 1989 [5], has been suggested to rationalize the protective effect of infections in autoimmune diseases [6, 7]. Preclinical observations and reports of animal studies further support the protective and ameliorative role of infections in autoimmune diseases. For instance, Bordetella pertussis infection results in the production of IL-10, an antiinflammatory mediator, which is claimed to be responsible for the protective effect of this bacterial infection on multiple sclerosis (MS) patients [8]. Hepatitis B virus, Epstein-Barr virus (EBV), Coxsackieviruses group B, lymphocytic choriomeningitis virus, Klebsiella pneumonia, Helicobacter pylori, and Schistosoma mansoni are among the viral, bacterial, and parasitic organisms that are reported to have protective effects against autoimmunity, besides stimulating the potential to induce autoimmunity [9–12].

From a different point of view, a mutual connection between infections and autoimmunity could be imaginable. As an example, patients with systemic lupus erythematosus (SLE) have been reported to be more susceptible to be infected with EBV, which is attributed to the impaired T cell response to fight and prevent latent infection [13]. On the other hand, animals administered with EBV nuclear antigen 1 (EBNA-1) demonstrated detectable levels of lupus-like autoantibodies [14]. Furthermore, patients with autoimmune diseases are prone to develop infections due to the immunosuppressive/immunomodulatory therapeutic agents, which are prescribed to them to control the hyperactivation of their immune system and inhibit autoimmunity.

While the scientific world has witnessed a considerable development in understanding the association of infections with autoimmunity, there are questions and uncertainties that remain to be elucidated. Despite the widely accepted notion that infections might provoke autoimmunity, there are obstacles that impede scientists from recognizing infection as a definite etiology in autoimmune diseases. For instance, the long period between the infection’s resolution and the incidence of autoimmune diseases, besides the remarkable role of genetics, which results in an altered immune response to infectious agents [15].

3: Autoimmunity and genetic syndromes

Immune system-related disorders have been reported in patients with genetic syndromes with various manifestations and at different severity degrees. With regard to the complicated and mostly unknown genetic background of immune system diseases, genetic syndrome models could serve as interesting tools and hold the key to determining responsible genetic components in causing immune system diseases, from primary immunodeficiencies to autoimmune disorders. Down syndrome [16–19], Di George syndrome [20], Kabuki syndrome [21], Klinefelter syndrome [22], Turner syndrome [23, 24], Noonan syndrome [25], and autoimmune polyglandular syndrome [26, 27] are of the genetic syndromes associated with immune defects and autoimmunity.

The first case of autoimmune thyroid disease (Hashimoto’s thyroiditis) in a Down syndrome patient was reported by Benda in 1946 [28]. Although there had been prior reports concerning the detectable levels of thyroid autoantibodies in patients with different genetic syndromes including Down syndrome, Benda reports was a turning point in considering the association of autoimmunity with aberrations and mutations in somatic chromosomes, as well as the X chromosome [28]. It is calculated that Down syndrome patients are 4–6 times more prone to develop autoimmune complications (celiac disease, autoimmune thyroid disease, and type 1 diabetes mellitus (T1DM) in particular), compared with those without Down syndrome [17]. This is of critical importance since autoimmune complications potentially reduce the QoL and decline the life expectancy of patients. Besides, autoimmune associated conditions contribute to a lower QoL and health status as well. For instance, infections (either as a result of immune dysfunction in Down syndrome patients or as an adverse effect of autoimmunity treatments) and malignancies (which is associated with autoimmunity in different aspects) are reported comorbidities of autoimmune disease.

Down syndrome, which occurs due to human chromosome 21 triplication, is known as the most frequent aneuploidy in the human with an incidence rate of about 1:300 to 1:1000 live births [OMIM #190685] [29]. Genetic analyses and molecular assays have put forward novel insights concerning the shared genetic components between autoimmunity and Down syndrome. AIRE gene, a pivotal factor in regulation of immune responses, is located on chromosome 21 [30]. In addition, interferon (IFN) receptor that binds to either type III IFN and interleukin (IL)-10, IL-22, and IL-26 cytokines consists of six subunits, among which four of them are encoded on chromosome 21 [31]. On the other hand, type I IFNs are involved in the pathogenesis of autoimmune diseases by the means of initiating JAK/STAT pathway activation. Type I IFN hyperactivity has been reported in Down syndrome and is attributed to the altered expression of type I IFN (as well as IFN-γ and IFN-α) due to their cytogenetic location on chromosome 21 [32]. Furthermore, number of genes have been detected to be located on chromosome 21, which are involved in the immune system such as ITGβ2, IFNAR1, IFNDR2, and ICOSL [16, 20]. Nevertheless, their overexpression as a result of gene dosage effect remained to be proven. In addition, some of the microRNAs (miRNAs) that regulate the expression of immune system factors are encoded on chromosome 21. Therefore, an additional chromosome 21 in Down syndrome potentially affect the expression of these factors, which in turn affect normal immune responses. Normal expression of miR-99a, let-7c, miR-125-b, miR-155, and miR-802, which contribute to normal T regulatory (Treg) cell development and macrophage-mediated immune responses, are disturbed in Down syndrome due to their cytogenic location on chromosome 21 [33]. Consequently, altered expression of innate immune system components such as Toll-like receptors (TLRs) and antiinflammatory genes are demonstrated in Down syndrome patients, which result in autoimmune manifestations besides immunodeficiency and poor response to vaccination [34]. Impaired TLRs’ pathways, chiefly TLR-2, has been reported in Down syndrome, which contributes to inappropriate response to infections and increased risk of chronic inflammation, both predispose individuals to autoimmune reactions [35]. Additionally, the microbiota contribute to the autoimmunity onset in Down syndrome patients. Obesity, improper nutritional and dietary habits, and lack of physical activity are all present in Down syndrome patients that contribute to microbiota dysbiosis, which is a leading cause of chronic inflammatory state in the body that can predispose individuals to further autoimmune complications [36].

Immune system diseases have been attributed to precocious aging in Down syndrome patients or the impaired immune system, which is due to some inborn errors of immunity that manifest as immunodeficiencies from the early ages [16]. However, reports concerning the lower incidence of opportunistic infections in adults with Down syndrome, compared with younger patients, differentiate this condition from primary immunodeficiency. Indeed, these observations could be due to altered epigenetic modification of the expression of responsible genes, which could be probably because of the extra chromosome 21 [20, 37]. Furthermore, it has been claimed that the patient’s immune system could reach a point of adequate maturation because of frequent exposure to different antigens [38]. However, underlying mechanisms of immune-related diseases, such as autoimmunity, in Down syndrome patients remain to be identified.

To address the issue of the increased chance of autoimmunity in Down syndrome patients, investigations into Treg cells have been initiated, considering the pivotal role of Treg cells in controlling immune responses. The thymus in Down syndrome patients has demonstrated anatomical and structural abnormalities, such as hypoplasia, cortical atrophy, and medullary enlargement that could affect the normal maturation process of T cells [18, 20]. On the other hand, T cell receptor excision circles (TREC), which are circular DNA molecules produced as by-products of T cell receptor (TCR) recombination and gene rearrangement were detected at lower levels in Down syndrome patients in comparison with healthy individuals [39]. The latter points to a dysfunctional turnover and development of T cells, which leads to early initiation of the senescence process in Down syndrome patients, while predisposing them to immune system dysregulation, dysfunction, and autoimmunity. Moreover, a dysfunctional thymus indicates an abnormal expression of responsible genes in the development of immune cells, such as AIRE, which predisposes the patient to develop autoimmunity [40]. Pellegrini et al. observed a peripheral overexpression of Treg cells with an impaired inhibitory potential, which in turn could lead to autoimmunity [41]. On the other hand, either the CD4  + or CD8  + T cells from Down syndrome patients have demonstrated resistance to Treg-mediated suppression, which has been indicated in autoimmune diseases, including SLE. This resistance has been imputed to the persistent exposure of immune cells to overproduced cytokines (e.g., TNF-α), even though the exact mechanism is not known so far [17]. Putting all the evidence together, immune dysregulation is considered as the main factor that induces a higher propensity to develop autoimmune diseases in Down syndrome individuals, although there is still controversy about whether the immune dysregulation originates from intrinsic defects of the immune system or happens following precocious senescence in these patients.

Autoimmunity has been reported in association with Turner syndrome, which occurs as a result of the complete or partial absence of one X chromosome. These patients are 2–3 times more susceptible than the normal population to develop autoimmune diseases [42]. For instance, autoimmune thyroid disease, IBD, celiac disease, T1DM, alopecia areata, and vitiligo are autoimmune conditions that could manifest in patients with Turner syndrome [24]. Enhanced exposure to estradiol (due to estrogen therapy) in these patients and the isochromosome iXq have been proposed as possible reasons for the increased incidence of autoimmunity in Turner syndrome. Considerable attempts have been made to clarify the underlying mechanisms of autoimmunity in Turner syndrome. Lee et al. detected a higher level of Treg cells in Turner syndrome patients compared with normal individuals, while these cells were not capable of inhibiting an autoimmune reaction properly [43]. Gawlik et al. have demonstrated a reduced percentage of Treg cells in girls with Turner syndrome associated with an autoimmune condition, whereas the percentage of Treg cells in healthy individuals and in Turner syndrome patients without any autoimmune complications were higher than in the first group [44]. Nonetheless, further investigations are required to elucidate the association of autoimmune diseases with Turner syndrome.

Several reports have reported different autoimmune conditions in patients with Klinefelter syndrome [45, 46]. However, there is not a systematic study to assess whether there is an association with autoimmunity. Recently, Seminog et al. conducted a retrospective study on Klinefelter patients, which resulted in reports concerning a higher risk for these patients of developing autoimmune conditions [47]. Interestingly, this increased risk was observed mainly in autoimmune diseases that are more frequent in women including MS, Sjogren’s syndrome, and SLE [47].

Impairments in the expression or activation of the rat sarcoma/mitogen-activated protein kinase (RAS/MAPK), which mediates the transduction of extracellular signals for regulating the cell cycle, growth, differentiation, death, and some inflammatory processes in the intracellular systems, could lead to induction of autoimmune processes [48, 49]. Mutation of contributing genes to this pathway results in a spectrum of genetic syndromes named RASopathies, of which Noonan syndrome (OMIM #163950) and Noonan-related syndromes are examples. Quaio et al. conducted a cohort study to survey the presence of autoantibodies and autoimmune manifestations in patients with RASopathies (Noonan syndrome in particular) [25]. They have reported that autoantibodies were detectable in the peripheral blood of patients and autoimmune diseases were frequently observed in association with Noonan syndrome [25]. These findings are consistent with the results of other investigations into Noonan syndrome-associated autoimmunity [50–52].

Kabuki syndrome (OMIM #147920 and OMIM #300867), which occurs due to mutations in either KMT2D or KDM6A genes (involved in epigenetic changes by histone modification), is a rare genetic disorder affecting different systems of the body [21]. Kabuki syndrome patients represent various abnormalities in the immune system including increased vulnerability to infections, low immunoglobulin levels, and some autoimmune reactions such as autoimmune thyroid disease, vitiligo, idiopathic thrombocytopenic purpura, and hemolytic anemia [53–55].

Regardless of the wide repertoire of reports in the context of higher incidence of autoimmune diseases in genetic syndromes, caution is warranted in interpreting these data since there are multiple factors that might confound the results. For instance, as these patients (e.g., Down syndrome or Turner syndrome patients) have various comorbidities and medical complications, their referral to the medical setting is more frequent than in the healthy population [56]; therefore, autoimmune diseases could be diagnosed at earlier stages and even at an asymptomatic level, which might lead to an overestimation of the incidence of autoimmunity in these patients. On the other hand, coexistence of the different medical conditions in these patients, besides the complicated diagnostic criteria of the number of autoimmune diseases, may result in the inclusion of a number of nonautoimmune patients, which could further overestimate the reported statistics [23].

4: Autoimmunity and inborn errors of immunity

Inborn errors of immunity (IEI) and autoimmunity have long been distinguished as two discrete medical conditions. However, the development of genetic analysis studies besides and the growing evidence concerning the immune regulatory pathways have put forward the notion if there is a mutual association between IEI and autoimmunity. Mutations and defects in a single gene could cause autoimmune manifestations. Meanwhile such defects are detectable in patients with IEI, which could manifest as immune dysregulation and subsequent autoimmunity, besides an enhanced susceptibility to infections that is commonly the main clue to IEI. Given the frequent reports regarding the presence of autoimmunity in IEI patients [57–61], investigating the shared genetic background, possible contributing mechanisms, and further probable complications is of interest.

Autoimmune complications affecting different organs and manifesting in a spectrum of severity have been reported in severe combined immunodeficiency (SCID), antibody deficiencies, combined immunodeficiencies (CIDs), gain of function (GoF) mutations in cytokine signaling pathways, and defects in innate immunity. Defects in both adaptive and innate immunity could manifest with autoimmunity, which has been reported in known immune deficiency syndromes; for instance, Omenn syndrome, severe combined immunodeficiency (SCID), hyper IgM syndrome, activated phosphoinositide-3-kinase δ syndrome (APDS), common variable immunodeficiency (CVID), STAT-1,3 GoF, Wiskott-Aldrich syndrome (WAS), Di George syndrome, and chronic granulomatous disease (CGD) [62–64]. On the other hand, mutations in genes that contribute to the pathways of immune regulation have been demonstrated to manifest with autoimmune symptoms, while the underlying disease is classified as IEI [62–64]. Autoimmune polyendocrinopathy, candidiasis, ectodermal dysplasia (APECED) [65], autoimmune lymphoproliferative syndrome (ALPS) [66], immunodysregulation, polyedocrinopathy, enteropathy, X-linked (IPEX) [67], LRBA deficiency [68], and CTLA-4 deficiency [69] are of the IEI with detected responsible mutation in immunoregulatory genes (AIRE, FAS and FASL, FOXP3, LRBA, and CTLA4, respectively).

Preclinical and animal studies on human monogenic immune-related disorders suggested that the defects of the immune system in IEI could stimulate tolerance breakdown, which in turn potentially initiates autoimmune processes [70]. SLE and rheumatoid arthritis (RA) are the two autoimmune diseases, which are best investigated in association with IEI. Genome-wide association studies (GWASs) on a population of 29,880 individuals have detected 98 out of 377 non-MHC candidate genes to contribute to a higher propensity to RA [71], among which 15 genes were of those have been already recognized in the context of IEI, particularly immunoregulatory genes [72]. Dysfunctional or abnormal development of T cells in the thymus potentially disturbs the central tolerance and therefore predispose the patient to autoimmunity following tolerance breakdown. This abnormal function of thymus has been reported in Di George syndrome and APECED [73, 74]. Nevertheless, impaired peripheral tolerance is chiefly attributed to dysfunctional Treg cells, which is remarkable in IPEX syndrome [75].

Besides the tolerance breakdown and defects in immune dysregulation (APECED, SCID, Omenn syndrome, WAS), as underlying etiologies that predispose patients with IEI to autoimmune manifestations, autoimmunity is reported in various forms of IEI as well. For instance, predominantly antibody deficiencies (X-linked agammaglobulinemia (XLA), CVID), disorders result from gain of function (GOF) mutations in cytokine signaling (STAT1 and STAT3 GOF), and innate immune defects (CGD) [62]. Although the autoimmunity mechanism in these diseases are not fully understood, presence of autoimmune manifestations are well documented. Meanwhile, studying autoimmunity in the context of IEI has resulted in further understanding of the contribution of different components of the immune system to the development of autoimmunity. For instance, it has been suggested that B regulatory cells (Bregs) are involved in mediating autoimmune manifestations in XLA patients. Studying autoimmunity in innate immune defects has highlighted the importance of oxidase pathways in controlling the inflammation, which in turn reduce the risk of autoimmunity [62].

Autoimmune manifestations in newborns and infants could direct the suspicion of physicians to IEI diagnosis, following the rule out of transferrable maternal defects. For instance, persistence early-onset autoimmune cytopenias lead to the diagnosis of Omenn syndrome, Di George syndrome, and some variants of SCID [64, 76]. In case of cytopenia associated with immune-mediated diabetes mellitus or hypothyroidism in neonatal patients, IPEX could be a probable diagnosis. Accordingly, autoimmune diseases in neonates and infants should put forward IEI as in differential diagnosis [64].

IEI should be diagnosed in the first months of life; otherwise, it could be life-threatening for the patient. Considering the increasing body of evidence about the underlying mechanisms and genetics behind the IEI and the development of diagnosis tools and treatment strategies, a remarkable number of IEI patients survive; therefore, developing autoimmune conditions in the later years of patients’ life could strongly affect the QoL of patients. On the other hand, series challenges appear in applying a proper treatment strategy, which should be beneficial in alleviating both immune deficiency symptoms and autoimmune manifestations. Collectively, autoimmunity imparts a massive burden on IEI patients and the related healthcare settings, in addition to negatively affecting the QoL of these patients. Hence, the importance of investigating autoimmunity in the context of IEI and the translation of the obtained data to clinical settings is highlighted.

5: Autoimmunity and malignancies

The association of autoimmunity and malignancy is bidirectional and multifaceted, while each could be followed by the other. Patients with autoimmune diseases have a tendency to develop specific types of malignancies, hematological malignancies in particular, which has been claimed to be as a result of immune system dysregulation in autoimmune diseases that could lead to cancer development. On the other side, some specific types of cancer are associated with autoimmune manifestations, which emerge either before or after the diagnosis of cancer. Autoimmune hemolytic anemia [77], systemic sclerosis [78], myositis [79], hepatitis [80], and neurological autoimmune syndromes [81] are of the autoimmune manifestations of malignancies. The term of paraneoplastic syndrome is indicative of the association of autoimmunity and specific types of cancer. Eaton-Lambert syndrome, paraneoplastic pemphigus, paraneoplastic arthritis, and palmar fasciitis are of the paraneoplastic syndromes with an autoimmune basis [82].

Moreover, autoimmune manifestations have been reported to appear after the diagnosis and the start of treatment, which is due to the adverse effects of cancer therapies such as immune checkpoint inhibitors [83]. Nevertheless, autoimmune diseases therapies such as disease-modifying antirheumatic drugs (DMARDs) and anti-TNF-α agents potentially increase the risk of cancer development as well. Although the theoretical mechanisms of the above mentioned associations are reasonable, conducted clinical trials and surveys have not reached a common conclusion and failed to reach a definite result whether the anticancer therapies increase the risk of autoimmunity or whether the autoimmune diseases’ treatment predispose individuals to develop cancer.

6: Autoimmunity and associated conditions affecting patients’ quality of life

Considering the chronicity of autoimmune diseases besides that there is no definite treatment for these patients, autoimmune diseases extensively affect the QoL of patients. In addition to the life-long period of receiving medications and facing different unwanted adverse effects, the association of autoimmune diseases with different condition such as cancers and infection could potentially lower the QoL of these patients. However, there are more factors that are affected by autoimmunity, which potentially contribute to more complications in autoimmune patients. For instance, infertility and recurrent abortion are conditions that could negatively affect the life of these patients. Antiphospholipid syndrome, an autoimmune condition either primary or secondary in association with SLE, is known as an important cause of recurrent spontaneous abortion [84, 85]. Furthermore, thyroid autoimmunity has been labeled as one of the important reasons leading to infertility and adverse pregnancy outcomes, such as preterm birth and spontaneous abortions, since it affect a considerable population of women in their fertility ages [86]. Several mechanisms have been suggestion in attempt to clarify the pathophysiology of infertility in autoimmune thyroid disease. Cross-reaction of thyroid antibodies with nonthyroid sites (e.g., placenta [87]) and coexistence of other autoimmune diseases that induce infertility (e.g., endometriosis, which has been recently introduced as an autoimmune condition due to the detectable autoantibodies and reported recurrent immune-mediated abortions [88, 89]) are of the suggested mechanisms.

Obesity, which has become a drastically growing epidemic [90], mediates an inflammatory state in the body that induces a high propensity to develop autoimmune diseases. Moreover, while altered microbiota composition and imbalance induce a great propensity for obesity in individuals, impaired microbiota is a facilitating factor in inducing autoimmunity [91]. The excess inflammatory state, resulting from the overall inflammatory state in obese individuals and the altered microbiota balance, impairs normal immune cells’ functions that potentially increase the risk of developing autoimmunity [92, 93]. Hence, obesity is associated with autoimmune diseases besides other metabolic disorders such as type 2 diabetes mellitus, atherosclerotic diseases, and nonalcoholic fatty liver disease (NAFLD), which potentially reduce the QoL of