ADCC, C′ activation, and formation of immune complexes because of the low affinity of IgG4 for Fc receptors, low capacity to activate C′, and its competition with other antibodies.
Regulatory Dendritic Cells
DCs are potent professional APCs with the dual roles of initiating adaptive immune responses against deleterious antigens and maintaining immunologic homeostasis by inducing antigen‐specific tolerance in the periphery [13]. Only immature DCs exhibit regulatory functions, and immature DCs are concentrated in the liver. Immunosuppressive cytokines or drugs, microbial products, interactions with Tregs or NKT cells, and phagocytosis of apoptotic blebs activate regulatory DCs (DCregs). DCreg presentation of peptide antigens to CD4 and CD8 T cells contributes to antigen‐specific tolerance by inducing T‐cell anergy, inhibiting T‐cell function, promoting generation of iTregs, and enhancing T‐cell apoptosis.
Immunoregulatory Interplay Between Treg and Th17 Cells
The interplay and balance between iTregs and pathogenic Th17 cells is pivotal for immunoregulation [14]. Low concentrations of IL‐2 promote iTreg proliferation and survival but are suboptimal for Th17 proliferation and differentiation. However, the adverse effects of low concentrations of IL‐2 on Th17 cells can be overcome by proinflammatory IL‐1β. Conversely, high concentrations of IL‐2 drive proliferation of CD4 and CD8 effector cells, including Th17 cells. iTregs also exhibit plasticity based on the cytokine milieu. TGF‐β promotes differentiation of either iTregs or Th17 cells by inducing expression of FOXP3 and receptor‐related orphan receptor (ROR)γ, respectively. The cytokine environment dictates differentiation toward either regulatory iTreg or the proinflammatory Th17 phenotypes. In the absence of IL‐6 and IL‐21 (Figure 2.2), FoxP3 binds to RORγ suppressing its transcriptional activity and preventing Th17 differentiation. In the presence of IL‐6 and IL‐21, FoxP3 dissociates from RORγ, allowing Th17 differentiation. Retinoic acid from gut DCs also suppresses Th17 cells, while expanding iTregs. The resulting balance between iTregs and Th17 dictates tissue immunopathology in autoimmune diseases.
In addition, iTregs and Th17 cells can undergo interconversion [14]. Thus, Th17 cells can convert to immunosuppressive IL‐10‐secreting cells, and FoxP3‐positive iTregs can convert to Th17 cells. Conversion of iTregs to Th17 cells requires a milieu containing IL‐1β, IL‐6, IL‐23, and TGF‐β. Activated epithelial target cells, including cholangiocytes, secrete cytokines favoring conversion of iTregs to Th17. Thus, target tissues can produce an imbalance of Th17 and iTregs, intensifying chronic inflammation.
Risk Factors for Autoimmune Diseases
Genetics
Complex Genetic and Monogenic Diseases
Complex genetic diseases require an interplay of genes and environmental factors that may manifest as more than one clinical disease (Figure 2.1) [1]. Overall, environmental exposures are more important than genetics in shaping the immune repertoire. Thus, a person's “exposome” – the lifelong sum of all endogenous and exogenous environmental exposures interacting with genetic and epigenetic factors – can favor autoimmunity or protect against it.
Genome‐wide association studies (GWAS) in autoimmune diseases, including AILDs, have demonstrated shared associations with HLA alleles and single nucleotide polymorphisms (SNPs) of genes related to innate immunity and adaptive immunity [15]. These include genes encoding interleukins, interleukin receptors, proinflammatory cytokines and their receptors, cytotoxic T lymphocyte antigen (CTLA)‐4 (a mediator of senescence and apoptosis of activated T cells), signal transducer and activator (STAT)‐4, chemokine receptors and CD69 (involved in migration of lymphocytes from lymph nodes and development of immunologic “memory”). However, odds ratios for each gene's contribution to risk for autoimmunity are quite small, suggesting that multiple SNPs are required for development of one or more of the 80 known autoimmune diseases.
HLA Risk Alleles
The strongest HLA‐associated risks for autoimmune diseases, including AIH and PSC, but not PBC, lie within the evolutionarily conserved 8.1 ancestral haplotype: HLA‐A1, Cw7, B8, TNFAB*a2b3, TNFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*03:01, DRB3*01:01, DQA1*05:01, DQB1*02:01 [2]. The extended 8.1 haplotype is the result of linkage disequilibrium, indicating an evolutionary advantage to sequestration of these alleles within class I, II and III HLA loci. These alleles are important for robust CD4 and CD8 T‐cell activation and generation of TNF‐α/β and C′ factors. The 8.1 haplotype is associated with AIH and PSC. Most Caucasians with HLA‐B8, DR3 have the 8.1 haplotype; however, recombinations have produced additional HLA‐DRB1*03:01 haplotypes associated with autoimmune diseases. It is notable that even healthy persons with the 8.1 haplotype exhibit an enhanced immunologic phenotype with autoantibodies, circulating immune complexes, activated T cells, and increased apoptosis of lymphocytes. The HLA‐DRB1 gene is of interest because it is the most polymorphic gene within the HLA class II region. Thus, it is not surprising that PBC is associated with the DR allele HLA‐DR8. Future studies are needed to define how different HLA alleles contribute to a break in tolerance and development of specific autoimmune diseases.
Non‐HLA Gene Associations
Interpreting the risks for autoimmune diseases conferred by non‐HLA genes is problematic because the odds ratios for risk of autoimmune diseases are far lower than those for HLA alleles [15]. Polymorphisms in genes encoding CTLA‐4, TNF‐α, Fas (CD95), TNF‐induced protein 3 (TNFAIP3), macrophage migration inhibitory factor (MIF), and SH2B adapter protein 3 (SH2B3) have been implicated in susceptibility to autoimmune diseases, including AILDs. CTLA‐4 is critical for downregulating effector immune responses and producing T‐cell senescence. TNF‐α is a potent proinflammatory effector cytokine and therapeutic target in specific autoimmune diseases. Dysfunction of genetic variants or deficient levels of TNFα‐induced protein 3‐interacting protein 1 (TNIP1) predispose normal innate cells to produce abnormal inflammatory responses to innocuous TLR ligands. TNFAIP3 is a modifying enzyme for ubiquitin, which may influence antigenicity of self‐proteins. CD95 (Fas) and CD95L (FasL) variants promote survival of autoreactive T and B cells and modify apoptosis of target cells. MIF is a proinflammatory cytokine in both innate and adaptive immunity. SH2B3 suppresses cytokine‐induced inflammation by downregulating Janus kinases (JAKs) and receptor tyrosine kinases (RTKs). Several autoimmune diseases also are linked to SNPs in cytokine and cytokine receptor genes. A pertinent example is the IL23R gene, which encodes a protein that forms a dimer with IL‐12Rβ1 to create the IL‐23 receptor complex required for IL‐23 induction of proinflammatory Th17 cells.
Critical Role of Epigenetics
Transcription Factor Enhancers and Super Enhancers
Gene transcription is an essential process in autoimmunity and autoimmune disease specificity. Emerging evidence indicates that the generation and perpetuation of autoimmunity is primarily driven by epigenetics [16]. Over 90% of the thousands of disease‐associated SNPs detected by GWAS are localized within non‐coding regions of DNA, that produce regulatory enhancers, sometimes occurring in clusters spanning 50 kb of DNA, called super enhancers (SEs). Multiple enhancers and SEs control the expression of protein‐coding genes. These enhancers, especially SEs, are especially important drivers of cell‐ and tissue‐specific genes. Enhancer functions are mediated through transcription‐factor (TF) binding motifs that require TF recruitment and nucleation of transcriptional machinery. Thus, enhancer activity depends on the local structure of chromatin responsible for the packaging of DNA in association with histone proteins. Since tightly packed DNA is inaccessible to DNA‐binding TFs, additional epigenetic mechanisms are required to render DNA accessible to enhancer TFs. These processes include methylation of DNA and posttranscriptional modification of histones through methylation, acetylation,