Unraveling the immunological puzzle of autoimmune hepatitis:pathogenesis, genetic triggers, and future directions

Abstract

Autoimmune hepatitis (AIH) is a chronic immune-mediated inflammatory liver disease characterized by progressive hepatocellular injury, circulating autoantibodies, hypergammaglobulinemia, and distinctive histopathological features. Although considerable advances have been made in understanding its immunopathogenesis, the precise mechanisms responsible for the initiation and progression of AIH remain incompletely elucidated. The disease results from a complex interaction among genetic susceptibility, environmental triggers, immune dysregulation, and impaired mechanisms of peripheral tolerance. Recent studies have highlighted the pivotal roles of autoreactive CD4⁺ and CD8⁺ T lymphocytes, dysfunctional regulatory T cells (Tregs), activated B lymphocytes, antigen-presenting cells, pro-inflammatory cytokines, and alterations in gut microbiota in driving persistent hepatic inflammation. Genetic predisposition is primarily associated with specific human leukocyte antigen (HLA) alleles, particularly HLA-DR3 and HLA-DR4, while numerous non-HLA genes involved in immune regulation have also been implicated. Environmental factors including viral infections, medications, herbal supplements, xenobiotics, and intestinal dysbiosis may trigger disease onset through molecular mimicry, bystander activation, or epitope spreading in genetically predisposed individuals. Advances in transcriptomics, proteomics, metabolomics, and single-cell sequencing have provided novel insights into immune cell heterogeneity and cytokine signalling pathways involved in disease progression. Conventional therapy using corticosteroids and azathioprine remains highly effective for most patients; however, treatment failure, relapse, and drug intolerance continue to present significant clinical challenges. Emerging therapeutic strategies targeting specific immune pathways, including biologics, Janus kinase inhibitors, Treg-based therapies, and precision medicine approaches, offer promising future directions. This review comprehensively discusses the immunological basis of autoimmune hepatitis, emphasizing its pathogenesis, genetic determinants, environmental triggers, immunological biomarkers, and innovative therapeutic perspectives while highlighting current knowledge gaps and future research priorities.