Autoimmune Liver Disease

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 (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.

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).

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.

Vitamin D deficiency is epidemiologically associated with risk of autoimmunity [19]. Achieving and maintaining high normal serum levels of vitamin D 3is a realistic and achievable goal, which could reduce the incidence and severity of autoimmune diseases.

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, and either deliberate infection with non‐pathogenic helminths or ingestion of specific parasite peptides to promote a systemic immunosuppressive Th2 environment [28].

Ingestion of antigens leads to absorption and interaction with the reticuloendothelial system of the liver. Repeated ingestion can result in oral tolerance, defined as the inability to respond to the ingested antigen when given parenterally [29]. Low doses of antigen induce iTregs, while higher doses create anergic tolerance. Studies involving the induction of oral tolerance to glutamic acid decarboxylase, the instigating autoantigen in T1DM, are ongoing. The applicability of oral tolerance depends on identification of disease‐specific initiating autoantigens; thus, it would be currently relevant in AILDs only for PBC and type 2 AIH.

At the time of diagnosis, the initiating events of most autoimmune diseases likely occurred months to years earlier and mechanisms of perpetuation are well established. This poses challenges for clinical management and focuses attention on therapeutic strategies to control inflammation, modify symptoms and signs, and retard progression. Progress in understanding the pathogenesis of autoimmune diseases provides rationales for additional conventional and novel therapies ( Table 2.3). Two therapeutic approaches warrant additional comment.

Studies of two strategies to produce iTregs specific for autoantigens are in progress ( Table 2.3) [1]. The first strategy is to increase the proliferation of existing iTreg populations by infusion of low doses of IL‐2, which is being studied in hematopoietic stem cell transplantation, graft‐versus‐host disease, T1DM, HCV‐associated vasculitis, and SLE. The second strategy involves generating antigen‐specific iTregs from peripheral blood mononuclear cells ex vivo for infusion. iTregs specific for CYP2D6 autoantigens in type 2 AIH have been produced, but not yet infused.

SNPs within enhancers, especially SEs, play dominant roles in autoimmune pathogenesis (see section Epigenetics) [16]. The theoretical fear that targeting epigenetic regulatory proteins might cause severe toxicity has not been observed with first‐generation inhibitors. Among SE proteins regulating genes associated with activation, stress and differentiation, the bromodomain and extra‐terminal (BET) family has emerged as a prime target for inhibition. BET inhibition decreased macrophage expression of inflammatory genes induced by lipopolysaccharide by preferentially inhibiting de novo expression of SE genes. BET inhibitors also blocked de novo SE gene expression in endothelial cells, markedly reduced CD4 Th cells differentiation to polarized subsets, and prevented effector cytokine production by already polarized Th cells. BET inhibitors also impacted B cells by inhibiting proliferation and ability to switch the isotype of their antibodies. More importantly, BET inhibitors have reduced inflammation and protected from disease in animal models of T1DM, MS, RA, and psoriasis. These data indicate that BET‐specific, and more generally SE‐related, mechanisms are promising therapeutic targets.

Table 2.3 Current and future therapeutic approaches to control autoimmune diseases.

AIH, autoimmune hepatitis; BAFF, B‐cell‐activating factor; CNI, calcineurin inhibitor; ERCP, endoscopic retrograde cholangiopancreatography; IL, interleukin; iTregs, inducible T regulatory cells; JAK, Janus kinase; MDSCs, myeloid‐derived suppressor cells; MS, multiple sclerosis; mTOR, mechanistic target of rapamycin; PIF, pre‐implantation factor; POC, proof of concept; PSC, primary sclerosing cholangitis; RA, rheumatoid arthritis; rHuIL‐10, recombinant human IL‐10; SLE, systemic lupus erythematosus; SOC, standard of care; T1DM, type 1 diabetes mellitus; Th, T helper cell; TNF, tumor necrosis factor.