HLA, gut microbiome and hepatic autoimmunity.

Genetic susceptibility to autoimmune liver diseases is conferred mainly by polymorphisms of genes encoding for the human leukocyte antigens (HLA). The strongest predisposition to autoimmune hepatitis type 1 (AIH-1) is linked to the allele , possession of which is associated with earlier disease onset and more severe course. In populations where this allele is very rare, such as in Asia, and in -negative patients, risk of AIH-1 is conferred by , which is associated with later disease onset and milder phenotype. AIH type 2 (AIH-2) is associated with . The pediatric condition referred to as autoimmune sclerosing cholangitis (ASC), is associated with the in populations of Northern European ancestry. is protective from AIH-1, AIH-2 and ASC in Northern European populations. Possession of the allele is associated with an increased risk of primary biliary cholangitis (PBC) across different populations. and confer susceptibility to primary sclerosing cholangitis (PSC), as well as and in Europe. The hepatic blood supply is largely derived from the splanchnic circulation, suggesting a pathophysiological role of the gut microbiome. AIH appears to be associated with dysbiosis, increased gut permeability, and translocation of intestinal microbial products into the circulation; molecular mimicry between microbial and host antigens may trigger an autoaggressive response in genetically-predisposed individuals. In PBC an altered enteric microbiome may affect intestinal motility, immunological function and bile secretion. Patients with PSC have a gut microbial profile different from health as well as from patients with inflammatory bowel disease without PSC.