**Background:** This editorial introduces a Research Topic published in Frontiers in Immunology focused on establishing the links between HLA and non-HLA genes in autoimmune liver disease (AILD) across diverse populations inclusive of different ages, races, and ethnicities. The collection comprises 4 laboratory-based investigations from Asia and Turkey, and 6 mini-reviews from the United States, United Kingdom/Europe, South America, and Canada. The primary autoimmune liver diseases addressed are autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC).
**Methods:** The collection includes original research articles and state-of-the-art mini-reviews summarizing current knowledge. Laboratory investigations employed genotyping, metabolomics, flow cytometry, and animal models. Huang et al. conducted a large cohort study of PBC patients from China. Yang et al. used metabolomics to identify inosine as a differentially abundant metabolite between DRB1*04:05 positive and negative Chinese AIH patients, followed by validation in a Con-A induced murine model of acute AIH. Yuksel et al. investigated regulatory B cells (B regs, CD20^pos^CD24^pos^CD38^pos^) and T regs in Turkish children with AIH. Ahuja et al. studied HLA and CTLA-4 CT60 polymorphisms in a North Indian AIH cohort. The mini-reviews synthesized existing literature on immunogenetics, epigenetics, microbiome interactions, and pediatric AILD.
**Key Results:** In PBC, Huang et al. reported that four disease predisposition HLA genes—DRB1*08:03, DRB1*07:01, DRB1*14:05, and DRB1*14:54—were present at high frequency, and the majority of patients had already developed cirrhosis, confirming the link between HLA genes and liver disease severity. A link between HLA genes and Lactobacillus was also noted, suggesting a possible role of microbiota in disease progression. Mulinacci et al. discussed environmental risk factors for PBC, including higher prevalence in urban areas with strong coal-mining heritage in North-east of England and clusters of PBC in New York City zip codes containing or adjacent to toxic waste sites. Yang et al. identified inosine as having immunomodulatory effects, highly altered between DRB1*04:05 positive and negative Chinese AIH patients. In a murine model, inosine demonstrated protective effects by attenuating hepatocyte apoptosis, preventing oxidative stress, and inhibiting activation and glycolysis of CD4^pos^ T effector cells. Yuksel et al. found that HLA-DRB*11 was most prominent in Turkish AIH patients. In children with AIH, immunosuppression severely reduced regulatory B cells, which were initially at higher frequency than in healthy controls, while naïve and activated T regs (CD4^pos^FOXP3^high^CD45RA^neg^) fluctuated over time. Tacrolimus was identified as a B reg-sparing drug. Cancado et al. explored the relationship between HLA-linked genetic markers of susceptibility and individual serological markers, using celiac disease as a prototype. Ahuja et al. reported an association of HLA-DRB1*03 and increased frequency of the GG genotype of CTLA-4 CT60 mutation in anti-SLA positive North Indian patients who were poor responders to immunosuppressive therapy. Mack reported data from the largest pediatric cohort at Kings College Hospital showing that HLA-DRB1*03 conferred the highest risk of AIH and autoimmune sclerosing cholangitis (ASC) compared to healthy controls. Beretta-Piccoli et al. noted that 80% of the blood supply to the liver is from the splanchnic circulation, supporting the role of gut microbiome, gut permeability changes, dysbiosis, and molecular mimicry in AILD development. Czaja summarized how epigenetics—including DNA methylation and miRNA—could influence AILD development and outcomes.
**Clinical Implications:** This collection reinforces that both HLA and non-HLA genes play critical roles in AILD susceptibility, severity, and treatment response. The identification of HLA alleles associated with disease progression (e.g., DRB1*08:03, DRB1*07:01 in PBC; DRB1*04:05 in AIH) may inform risk stratification. The protective effect of inosine in murine AIH suggests potential for future therapy in acute AIH. The finding that tacrolimus is B reg-sparing has implications for immunosuppressive regimen selection in pediatric AIH. The association of CTLA-4 polymorphisms with poor treatment response in North Indian patients highlights the importance of genetic profiling for personalized therapy. Emerging therapeutic strategies discussed include antigen-specific immunotolerance using tolerogenic vaccines and nanotechnology-based tolerogenic immune-modifying nanopeptides for PBC, as well as epigenetic modulation for drug development. The editors conclude that this collection provides updated knowledge on HLA and non-HLA genes in relation to AILD, with focus on AIH and PBC, particularly from regions where such data was not previously available.