Cellular and Molecular Mechanisms of Autoimmune Hepatitis

Abstract

Autoimmune hepatitis is an uncommon idiopathic syndrome of immune-mediated destruction of hepatocytes, typically associated with autoantibodies. The disease etiology is incompletely understood but includes a clear association with human leukocyte antigen (HLA) variants and other non-HLA gene variants, female sex, and the environment. Pathologically, there is a CD4+ T cell-rich lymphocytic inflammatory infiltrate with variable hepatocyte necrosis and subsequent hepatic fibrosis. Attempts to understand pathogenesis are informed by several monogenetic syndromes that may include autoimmune liver injury, by several drug and environmental agents that have been identified as triggers in a minority of cases, by human studies that point toward a central role for CD4+ effector and regulatory T cells, and by animal models of the disease. Nonspecific immunosuppression is the current standard therapy. Further understanding of the disease's cellular and molecular mechanisms may assist in the design of better-targeted therapies, aid the limitation of adverse effects from therapy, and inform individualized risk assessment and prognostication.

Critical roles of conventional dendritic cells in autoimmune hepatitis via autophagy regulation

“…Autoimmune hepatitis (AIH) is a chronic necroinflammatory disease of the liver that is characterized by histological interface hepatitis, hypergammaglobulinemia and the production of autoantibodies and could rapidly lead to cirrhosis and end-stage-liver disease if left untreated 1 . During AIH, self-tolerance (also termed homeostatic processes) is impaired, resulting in Kupffer cell (KC)-, neutrophil-, monocyte-, and T-cell-mediated inflammatory and immune reactions, which are implicated in the pathogenesis of autoimmune liver injury 2,3 . However, the vital role of conventional dendritic cells (DCs) in the initiation and extension of AIH is not fully understood.…”

Review article: experimental therapies in autoimmune hepatitis

“…Non‐HLA associations, including immune regulation or signalling pathways such as cytotoxic T lymphocyte antigen 4, 48‐50 the transcription factor STAT4, 51 SH2B3, 2 Fas 52 and the vitamin D receptor, 53,54 and several cytokine pathways, including TNFα 55,56 and transforming growth factor‐β, 57 among others, have been described. A range of environmental factors have been suggested to trigger autoreactive immune responses resulting in the loss of self‐tolerance in susceptible individuals, including drugs and viral infections 58 …”

Pathogens and autoimmune hepatitis

“…The main features of AIH is an interface hepatitis, presence of autoantibodies against liver autoantigens and elevated immunoglobulin (Ig)G and aminotransferase levels. However, the clinical spectrum is variable, and ranges from asymptomatic presentations to severe hepatitis with features similar to acute viral hepatitis or fulminant hepatic failure . In addition, the existence of so‐called overlap syndromes of AIH with other autoimmune liver diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), make a conclusive diagnosis of AIH somewhat difficult .…”

“…These T cells might have a lower avidity to the host protein that confers molecular mimicry than to the original viral antigen (3). Nevertheless, as the main target of the aggressive anti-viral immune response has disappeared, the remaining cross-reactive T cells now attack non-infected hepatocytes carrying the similar self-protein, resulting in AIH (4). Due to the presumably lower avidity of crossreactive T cells to the self-epitope, this auto-destructive process may take a rather long time.…”