As discussed earlier, epigenetics plays a crucial role in regulating TFs in innate and adaptive immune responses involved in autoimmune diseases and determining specificity for different cell types and tissues [16]. While the mechanisms already discussed focus on factors leading to autoantigen recognition, it is now clear that epigenetics dictates the subsequent obligatory failure to regulate and terminate autoimmune reactions. GWAS showed that SNPs associated with immune‐mediated diseases encode enhancers and SEs that cluster within the immunoregulatory regions of immune cells. Indeed, analysis of the causal variants in 21 autoimmune diseases showed that 60% of SNPs mapped to immune cell enhancers and eRNA induced by immune cell activation. Disease‐specific profiles are beginning to be recognized. For example, T1DM‐associated SNPs are present in enhancers active in the thymus, T cells, B cells, and hematopoietic stem cells. The finding that SNPs for SEs in CD4 Thf cells are present in multiple autoimmune diseases, including T1DM, MS, RA, celiac sprue, and ulcerative colitis, strongly indicates their importance in pathogenesis. In addition, epigenetics controls suppression of autophagy, which dysregulates immune modulation in effector cells and promotes persistence of cytokine‐activated target cells/tissues in autoimmune diseases.
MicroRNA
Numerous studies indicate that miRNAs are important epigenetic regulators of proteins and networks involved in the generation and perpetuation of autoimmunity [17]. The mechanisms contributing to progressive autoimmunity include hyperactivation of innate macrophages and DCs, hyperstimulation of autoreactive T cells, inhibition of apoptotic elimination of autoreactive T and B cells, and alteration of regulatory balance. The impact of miRNAs alters the balance between pathogenic Th17 and iTregs by promoting dominance of Th17 cells.
Epitope Spreading
Autoimmunity begins with loss of tolerance to a specific autoantigen, but later expands to include reactions to additional autoantigens, a phenomenon called epitope spreading [1]. By extending the autoreactive T‐cell and B‐cell repertoire mediating autoimmune disease, epitope spreading greatly reduces the prospect that host immunoregulatory mechanisms can resume control. The causes of epitope spreading are poorly defined but may involve failure of normal anti‐inflammatory mechanisms of apoptosis or other forms of efferocytosis to prevent presentation of autoantigens. The hypothesis that apoptosis is involved in epitope spreading is attractive because apoptotic blebs do not contain random samples of intracellular constituents, but instead contain high concentrations of known autoantigens.
Tissue Memory T Cells
Tissue‐resident memory T (TRM) cells are a newly identified subset of non‐circulating antigen‐specific memory T cells that persist long term in epithelial barriers (e.g. skin, lung, gut and reproductive tract) and in brain, kidney, joints, and pancreas [25]. TRM cells are distinct from circulating memory T cells and provide immediate protective responses upon reexposure to antigens. However, autoreactive TRM cells have been implicated in chronic autoimmune diseases, including AIH, vitiligo, psoriasis, and RA. The longevity and privileged location of autoreactive TRM cells within tissues favors perpetuation of autoinflammation and tissue destruction.
Cytokines Promoting Chronic Inflammation and Autoimmunity
IL‐12 Family
The family of IL‐12 cytokines – IL‐12, IL‐23, IL‐27 and IL‐35 – are secreted by activated innate DCs and macrophages [1]. Each cytokine can perpetuate autoimmune inflammatory diseases by regulating CD4 T‐cell subsets in the adaptive immune response (Figure 2.2). IL‐12 and IL‐23 are among the most potent proinflammatory cytokines, while IL‐27 and IL‐35 are anti‐inflammatory and immunosuppressive. IL‐12 drives initial and subsequent differentiation of naive CD4 Th0 cells into Th17 cells and γδ T cells to produce inflammatory IL‐17. Recent studies indicate that IL‐21, secreted by Thf and Th9 cells, is the most dominant factor in the generation and maintenance of immunopathology (Figure 2.2).
IL‐20 Receptor Cytokines
IL‐19, IL‐20 and IL‐24 signal through the IL‐20RA/RB receptor complex [26]. Theses cytokines are expressed by both immune and epithelial cells and result in bilateral stimulation. These cytokines have a dual potential to immunoregulate innate and adaptive immune responses or to promote immunopathogenesis. These cytokines are most often pathogenic in autoimmune diseases, perpetuating chronic tissue inflammation.
Tertiary Lymphoid Structures and Germinal Centers
Tertiary lymphoid structures (TLSs) frequently develop in autoimmune diseases that contain T‐cell and B‐cell zones capable of producing adaptive cellular and humoral immune responses [27]. TLSs portend poor prognosis due to increased autoactivation of T‐ and B‐cell clones. Excessive production of autoantibodies against initiating autoantigens and those involved with epitope spreading augment antibody‐mediated cytotoxicity during the evolution of autoimmune diseases (Figure 2.2). In addition, APC phagocytosis and processing of immune complexes composed of autoantigens and autoantibodies dramatically increase the quantity of autoantigen‐specific CD8 CTLs. Tfh cells and their signature cytokine IL‐21 drive B‐cell production of high‐affinity autoantibodies, differentiation of memory B cells, and APC functions of activated B cells within the expanded number of germinal centers in TLSs.
Epithelial Cell‐induced Transformation of iTreg to Th17 Cells
As discussed earlier, cytokines produced by MAIT cells can stimulate epithelial cells, including cholangiocytes, to secrete IL‐6, IL‐1β, IL‐23 and TGF‐β [7]. This combination of cytokines can transform iTregs into activated Th17 cells that promote a proinflammatory Th17‐mediated inflammation (Figure 2.2).
Prevention of Autoimmunity and Therapeutic Control of Autoimmune Diseases
Overview
Our current understanding of the mechanisms involved in the generation and perpetuation of autoimmunity provide conceptual as well as realistic targets for interventions to prevent and treat autoimmune diseases [1]. Clearly, genetic and epigenetic SNPs and environmental exposures cannot be eliminated as risk factors. However, it may become possible to identify children at risk of autoimmunity and develop strategies to reduce their risk of autoimmune diseases. The development of new immunosuppressive medications, inhibition of cytokine production and function, and epigenetic inhibitors increase the probability of controlling a variety of autoimmune diseases in the near future.
Strategies to Prevent Autoimmunity
Vitamin D3
Vitamin D deficiency is epidemiologically associated with risk of autoimmunity [19]. Achieving and maintaining high normal serum levels of vitamin D3 is a realistic and achievable goal, which could reduce the incidence and severity of autoimmune diseases.
Gut Microbiota Manipulation in Pregnancy and Infancy
It remains unclear if changes in the fecal microbiota associated with specific autoimmune diseases represent causes or effects [20]. Were causal relationships identified for either initiation or perpetuation of autoimmunity, several strategies theoretically could decrease the risk of autoimmunity, especially if used during pregnancy and infancy. These include probiotics to shape the evolution of the gut microbiota and sustain the mucosal barrier, fecal microbiota transplantation to create a preventive gut microbiome,