Diego Vergani

Autoimmune hepatitis (AIH) is typically a chronic, inflammatory, and progressive liver disease of autoimmune origin. Currently, two recognized types are identified in clinical practice: type 1 and type 2. The disease can occur in all geographic regions and racial/ethnic groups worldwide, but shows marked variations. This pattern reflects a complex interplay between genetic factors and environmental triggers. In this review, we aim to examine the geoepidemiological features of AIH and explore how these features relate to its etiopathogenesis, providing an integrated analysis of this complex condition. Our work may shed light on the initiation and progression of AIH, as well as its treatment and prevention.

Autoimmune hepatitis (AIH) is a rare chronic inflammatory liver disease characterized by the presence of autoantibodies, including those targeting O-phosphoseryl-tRNA:selenocysteine-tRNA synthase (SepSecS), also known as soluble liver antigen (SLA). Anti-SepSecS antibodies have been associated with a more severe phenotype, suggesting a key role for the SepSecS autoantigen in AIH. To analyze the immune response to SepSecS in patients with AIH at the clonal level, we combined sensitive high-throughput screening assays with the isolation of monoclonal antibodies (mAbs) and T cell clones. The anti-SepSecS mAbs isolated were primarily IgG1, affinity-matured compared with their germline versions, and recognized at least 3 nonoverlapping epitopes. SepSecS-specific CD4 ⁺ T cell clones were found in patients with AIH who were anti-SLA-positive and anti-SLA-negative,and, to a lesser extent, in patients with non-AIH liver diseases and in healthy individuals. SepSecS-specific T cell clones from patients with AIH produced IFN-γ, IL-4, and IL-10, targeted multiple SepSecS epitopes, and, in one patient, were clonally expanded in both blood and liver biopsy. Finally, SepSecS-specific B cell clones, but not those of unrelated specificities, were able to present soluble SepSecS to specific T cells. Collectively, our study provides the first detailed analysis of B and T cell repertoires targeting SepSecS in patients with AIH, offering a rationale for improved targeted therapies.

Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine, and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumour necrosis factor-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.

Imbalance between T regulatory (Treg) and T effector (Teff) cells is likely to contribute to the induction and perpetuation of liver damage in autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (AISC) either through inability of Tregs to restrain proliferation and effector cytokine production by responders or through conversion of Tregs into T helper type 1 (Th1) or type 17 (Th17) effector lymphocytes. We investigated the effect of Treg skewing on the phenotypic and functional properties of CD4⁺CD127⁺CD25^high cells, an activated subset of Teff, in 32 patients with AIH and 20 with AISC and in 36 healthy subjects. In AIH/AISC we noted a substantial increase in peripheral blood–derived CD4⁺CD127⁺ CD25^high cells that display a Th1/Th17 phenotypic profile, as reflected by heightened interferon gamma and interleukin 17 (IL‐17) production as well as by high levels of T‐bet and related orphan receptor 3 expression, which is strongly correlated with disease activity. CD4⁺CD127⁺CD25^high cells are unresponsive to low‐dose IL‐2 and in patients have marked proliferative ability, further enhanced by stimulation with IL‐7. CD4⁺CD127⁺CD25^high cells obtained from CD4⁺ cells exposed to Treg polarizing conditions display enhanced IL‐10 production; up‐regulate CD49b and LAG‐3, markers of T regulatory 1 cells; and effectively suppress responder cell proliferation in both healthy subjects and AIH/AISC patients through a mechanism which is dependent on interferon gamma and IL‐17. The suppressive function of CD4⁺CD127⁺CD25^high cells is maintained upon proinflammatory challenge in healthy subjects but not in AIH/AISC. Conclusion: Treg skewing confers activated Teff phenotypic and functional properties of T regulatory 1 cells in health and in AIH/AISC, though suppressive function is lost in patients upon proinflammatory challenge; protracted modulation of the inflammatory environment is required to attenuate the effector potential while boosting immunoregulatory properties in Teff. (Hepatology 2017;66:1570–1584).