The Immunogenetics of Autoimmune Cholestasis

Abstract

The immune-mediated hepatobiliary diseases, primary biliary cirrhosis and primary sclerosing cholangitis are relatively rare, albeit and account for a significant amount of liver transplant activity and liver-related mortality globally. Precise disease mechanisms are yet to be described although a contributory role of genetic predisposition is firmly established. In addition to links with the major histocompatibility complex, a number of associations outside this region harbor additional loci which underscore the fundamental role of breaks in immune tolerance and mucosal immunogenicity in the pathogenesis of autoimmune biliary disease. We provide an overview of these key discoveries before discussing putative avenues of therapeutic exploitation based on existing findings.

Keywords: Autoimmune liver disease; Autoimmunity; Mucosal immunity; Primary biliary cirrhosis; Primary sclerosing cholangitis.

Fig. 1

Aggregation of genetic risk in complex diseases. PBC and PSC represent complex diseases, in which the cause is attributed to presence of ostensible genetic risk factors that exhibit a poorly understood interaction with coexisting environmental influences. Individual susceptibility factors are frequently nonpathogenic in isolation, and currently identified genetic variants frequently occur in the healthy population to a certain degree. However, in an individual who is immunologically primed, the cumulative loss of an unfortunately high burden of protective factors gives rise to breaks in immune tolerance (indicated by holes) that predispose to autoimmunity (eg, dysregulated IL-2 or IL-12 signaling pathways) in addition to pathogenic responses to the commensal microbiome (eg, CARD-9 variants) that result in a clinically identifiable presentation. Additional modifier genes or epigenetic influences may also exist, which influence the rate of progression and variant clinical phenotypes (eg, Fut-2 polymorphisms).

Fig. 2

Mucosal genetics in autoimmune cholestatic liver disease. The strongest genetic associations in autoimmune cholestatic liver disease are within the MHC. However, a significant proportion of non-HLA associations and epigenetic influences underscore the importance of mucosal immunogenicity in the pathogenesis of autoimmune cholangitis. These associations include defective microbial handling and immunopathogenic responses to the commensal microbiome, defects in epithelial (eg, intestinal or biliary) barrier function, dysregulated leukocyte trafficking and homing to sites of injury, loss of intestinal and hepatobiliary tolerogenic responses, and consequently direct tissue inflammation. The outer (green) ring in this diagram indicates the putative mucosal pathway, with PSC risk genes identified by the middle (blue) ring and PBC risk genes the inner (red) ring.