Influence of genes, sex, age and environment on the onset of autoimmune hepatitis

Abstract

The pathogenesis of autoimmune hepatitis (AIH) is complex. However, it is believed that a susceptible individual, owing to his genetic background, sex and age, can develop the disease following exposure to an environmental trigger. Autoimmune hepatitis does not follow a Mendelian pattern of inheritance; hence no single causative genetic locus has been identified. However, several genes, inside and outside the HLA locus, have been linked to an increased susceptibility to AIH. Epidemiological evidence also suggests that the sex and age of the patient plays a role in AIH pathogenesis as the disease onset occurs mainly in the two first decades of life and a higher disease incidence is observed in females. No environmental trigger has been identified, but several have been proposed, mainly viruses and xenobiotics. This article aims at reviewing the current knowledge on susceptibility factors leading to AIH and putative triggers, emphasizing fundamental mechanisms responsible for the break of liver immunological tolerance.

Figure 1

Pathogenesis of autoimmune hepatitis (molecular mimicry hypothesis). AIH can occur in an individual of a particular sex and age with a genetic background of susceptibility. To develop AIH, this individual must encounter an environmental trigger such as an infection or exposure to a xenobiotic. This will induce an immune response and secretion of pro-inflammatory molecules resulting in the elimination of the pathogen. However, this response may also lead to an immune cross-reactivity with liver proteins with an efficient activation of autoreactive cells leading to a break of immunological tolerance towards the liver.