Tregs. FoxP3 Tregs secrete immunoregulatory and immunosuppressive cytokines, including, IL‐9, IL‐35, IL‐10 and transforming growth factor (TGF)‐β. These cytokines immunosuppress activated CD4 and CD8 T cells and promote T‐cell anergy by downregulating APC expression of costimulatory CD80 and CD86. In addition, Treg upregulation of intracellular cyclic AMP directly inhibits cell proliferation and reduces production of IL‐2 required for T‐cell proliferation.
Natural and Inducible T Regulatory Cells
Tregs are classified as natural Tregs (nTregs) or inducible Tregs (iTregs) [11]. nTregs are produced in the thymus and represent 5–10% of the total CD4 T‐cell population. Despite having a relatively high affinity for autoantigens, nTregs escape clonal deletion in the thymus. In the periphery, nTregs act as autoantigen‐specific sentinels within the lymph nodes and spleen to maintain peripheral tolerance. They do so by inhibiting autoantigen activation of T cells by APCs, causing direct cytotoxicity of autoantigen‐activated T cells and secreting anti‐inflammatory cytokines IL‐10 and TGF‐β.
iTregs are a subset of CD4 T cells activated in the periphery (Figure 2.2). When naive CD4 T cells (CD4 Th0 cells) are activated in the presence of IL‐10, IL‐4 and TGF‐β, they differentiate into antigen‐specific CD4, CD25, FoxP3 iTregs. Both foreign antigens and autoantigens can generate antigen‐specific iTregs, conferring immunoregulatory importance in both normal immunity and autoimmunity. iTregs suppress effector CD4 T‐cell subsets and cytotoxic CD8 T cells by secreting immunosuppressive IL‐10 and TGF‐β, inducing cell cycle arrest and effector T‐cell apoptosis. In addition, iTregs block the costimulation and maturation of DCs. Among iTregs (Figure 2.2), the T regulatory 1 (Tr1) subclass exclusively secretes IL‐10 but does not express FoxP3. In contrast, the T helper 3 (Th3) subclass exclusively secretes TGF‐β.
Peripheral B‐cell Regulatory Mechanisms
Activated B regulatory cells (Bregs) also secrete immunosuppressive cytokines IL‐10, IL‐35 and TGF‐β. IL‐10 and IL‐35 render CD4 Th1 and Th17 cells incapable of mediating immunopathology or producing proinflammatory cytokines [12]. In contrast, Breg secretion of TGF‐β promotes antigen‐activated CD4 T‐cell differentiation into iTregs (Figure 2.2), secreting IL‐10 that inhibits TNF‐α production. Additional mechanisms also contribute to B‐cell immunoregulation. Secreted IgM induces anti‐inflammatory apoptotic bodies to reduce proinflammatory cytokines. Contact between B and CD4 T cells reduces CD4 T‐cell proliferation and secretion of Th1. Binding of B cell CD95L (Fas ligand) to CD95 (Fas) on T cells induces T‐cell apoptosis. Secretion of autoantigen‐specific IgG4 inhibits 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
