also interact directly with transcriptional mechanisms and enhancer DNA can also generate enhancer RNA (eRNA) to increase the amount of enhancer proteins. Epigenetic long non‐coding RNAs (lncRNAs) are expressed within innate immune cells and CD4 Th1, Th2, Th17, Tregs, CD8 and B cells. lncRNAs directly regulate activation and functions of immune cells. lncRNAs promote susceptibility to autoreactivity and perpetuation in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), and psoriasis.
MicroRNAs
MicroRNAs(miRNAs) function epigenetically as posttranscriptional and posttranslational regulators of gene expression [17]. miRNAs and TFs regulate each other's expression in feedback loops: TFs are negatively regulated by miRNAs, while miRNAs are positively regulated by TFs. Compelling evidence indicates that miRNAs control the activation state of innate macrophages and DCs, activation of T cells, apoptotic elimination of activated T and B cells, and the critical balance between iTregs and Th17 cells in sites of inflammation. To date multiple miRNAs have been implicated in the immunopathogenesis of autoimmune diseases, including AILDs.
Sex and Sex Hormones
Most autoimmune diseases have a female predilection [1,18]. However, PSC is a notable exception among AILDs (Table 2.1). Sex is genetically binary and imprinting of XX female and XY male genomes occurs in all cells from embryogenesis throughout life [18]. Both innate and adaptive immune cells have sex hormone receptors, and sex hormones contribute to the development and activity of the immune repertoire (Figure 2.1). Yet it is unclear whether female predominance in autoimmune diseases reflects regulatory mechanisms related to sex‐linked genes, sex‐specific hormones or a combination of both. Females normally produce higher titers of antibodies, more autoantibodies and greater cell‐mediated immunity to infections and immunization than do normal males. In addition, there is a gender bias in AIRE expression in the thymus, which may impact deletion of autoreactive clones and formation of nTregs and Bregs. Estrogen levels are also immunoregulatory: high levels inhibit CD4 Th1‐mediated cellular responses and promote CD4 Th2 antibody‐mediated responses. Prolactin, progesterone and testosterone also regulate immune responses by modulating expression of estrogen receptors and altering cytokine secretion. However, the effects of estrogen and other sex hormones in adult women do not explain the female predilection for autoimmunity in children or elderly adults. Postulated explanations include skewed X chromosome activation, X monosomy, and microchimerism. Beginning during embryogenesis and continuing through life, either the maternal or paternal X chromosome within each cell is inactivated, forming a Barr body adjacent to the nucleolus. Thus, females are a mosaic of two cell types, based on the parental source of the active X chromosome. Skewing of X inactivation varies widely and increases with age. Thus, some X‐linked autoantigens might theoretically escape central or peripheral tolerance. The proximity of Barr bodies to the nucleolus suggested that they may interact to expose cryptic autoantigens. X monosomy might promote autoimmunity by preventing tolerance to autoantigens encoded by both X chromosomes. Entry of fetal hematopoietic stem cells into the maternal circulation during pregnancy can cause fetal–maternal microchimerism that could promote loss of self‐tolerance.
Vitamin D and Sunlight Exposure
In addition to its roles in bone mineralization and calcium homeostasis, vitamin D modulates immune reactions and risk for autoimmunity [19]. Both vitamin D deficiency and genetic polymorphisms in the vitamin D receptor (VDR) increase the incidence and severity of multiple autoimmune diseases. Conversely, high vitamin D levels reduce the risk of MS. Reduction in sunlight exposure and synthesis of 1,25‐dihydroxyvitamin‐D3 (D3) might explain, in part, the strong correlation between the incidence of autoimmune disease and increasing latitude.
SNPs in two VDR genes, BsmI and TaqI, are associated with AILDs. SNPs in these genes and FokI are associated specifically with AIH. Dietary vitamin D and vitamin D synthesized in response to ultraviolet‐B radiation in sunlight determine serum vitamin D levels. Sequential hydroxylation in the liver and kidney produce D3, the most potent ligand for VDRs. Innate and adaptive immune cells express VDRs that induce multiple immunologic effects. For example, D3 regulates production of antimicrobial peptides and reactive oxygen species in innate immune cells and promotes NKT cell immunomodulatory functions. D3 also downregulates immunopathogenic CD4 Th1 and Th17 cells, while upregulating immunosuppressive CD4 Th2 cells and iTregs. By reducing Th1 secretion of IL‐2, D3 not only inhibits proliferation of CD4 and CD8 effector T cells but also generates low IL‐2 levels, favoring proliferation of functional iTregs.
Loss of Immune Tolerance to Autoantigens and Perpetuation of Autoimmune Diseases
Overview
Autoimmune diseases are uncommon, despite the high frequency of genetic susceptibility and environmental exposure to microbial pathogens and xenobiotics, including drugs. Autoimmunity requires four essentials. First, environmental triggers are required to initiate loss of tolerance to autoantigens in susceptible individuals (Figure 2.1). Second, the individual must have HLA alleles that facilitate autoantigen activation of T cells. Third, T cells must express autoreactive TCRs. Fourth, the individual must fail to immunoregulate the response to autoantigens. Evidence that low levels of autoimmune reactions are common in healthy people highlights the fact that these initial steps are common but only deleterious when not immunoregulated. GWAS indicates that failure to immunoregulate an autoimmune reaction is dictated by epigenetic SNPs for enhancers and SEs of gene expression more than SNPs for HLA and non‐HLA proteins. Moreover, these SNPs are critical drivers of the cell and tissue specificity of autoimmune diseases. Multiple factors and mechanisms to break tolerance to self‐antigens have been identified.
The increasing incidence of autoimmunity and inflammatory diseases observed worldwide is correlated with changes in environmental factors, including a more modern lifestyle, improved hygiene, a Western diet, use of antibiotics, and elimination of childhood parasitic infections. Each of these affect the composition and function of the gut microbiota. Although the proposed causal link between the gut microbiome and autoimmunity has not been proved, available data indicate that interplay between the gut microbiota and the innate and adaptive immune systems of the intestine and liver plays key roles in both normal and dysfunctional systemic immunity.
Role of the Microbiome
The gut microbiome has been implicated in autoimmunity (Figure 2.1) [20]. The gut microbiota change dynamically under the influence of aging, sex hormones, diet, water purity, hygiene, sanitation, pollution, exposure to pathogens, use of antibiotics, and the integrity of the gut–blood barrier. Gut microbiota are composed of commensal bacteria, fungi and viruses, as well as potentially pathogenic bacteria and fungi. In addition, the microbiota process food, xenobiotic pollutants and drugs to generate micronutrients and metabolites. Intestinal immune responses and the leakiness of the mucosa dictate the types and concentrations of PAMPs, DAMPs, cytokines, microbes, and food antigens entering the portal vein for processing in the liver. PAMPs and DAMPs stimulate enterocyte inflammasomes leading to secretion of proinflammatory cytokines. As discussed earlier, bacterial metabolites of vitamin B are the activating antigens for MAIT cells. Thus, the gut microbiome and intestinal immune responses appear to influence systemic immunity, and risk for autoimmunity, through the innate and adaptive immune responses of the liver.
Altered composition of the gut microbiota, referred to as “dysbiosis,” has been reported in autoimmune diseases, including AILDs. Whether dysbiosis is the cause or the effect of autoimmunity remains a key unresolved issue. Female sex hormones can also alter the gut microbiome, which may contribute to the female predilection in autoimmunity. If an altered gut microbiota or increased gut permeability were causally related to autoimmune diseases, then restoration of a normal microbiota