Autoimmune hepatitis (AIH) is believed to begin when the immune system loses tolerance to the liver’s own antigens — the self-molecules it normally leaves alone. The loss is not a single event but the combined effect of several mechanisms acting together, which is why no one trigger has been identified. Once tolerance is lost, T cells and the cells around them injure the liver’s parenchymal cells, the hepatocytes.
How tolerance is lost
Molecular mimicry is the starting point for several of the proposed routes: a foreign antigen, often from an infection, resembles a self-antigen closely enough that the immune response raised against the foreign one also recognises the liver’s own tissue. Cytokine over-production, an excess of the signalling proteins that immune cells use to communicate, then shifts the local environment toward inflammation. An inherited MHC predisposition makes the presentation of self-antigens to T cells more likely to provoke a response; MHC (major histocompatibility complex) molecules are the surface proteins that display antigen fragments to T cells. Finally, regulatory T cells (Treg cells) — the cells that normally restrain auto-reactive lymphocytes — are reduced in number or fail in function, so the response is no longer held in check. These mechanisms are believed to act at the same time as one another rather than in sequence.
A molecular mimicry example: anti-LKM1
One subtype of AIH is marked by anti-LKM1 (anti-liver kidney microsomal-1), an autoantibody directed against CYP2D6, a cytochrome P450 enzyme in the liver. Parts of the CYP2D6 peptide sequence resemble sequences in HSV-1 (herpes simplex virus 1), CMV (cytomegalovirus) and HCV (hepatitis C virus), and this homology is the proposed link between those infections and the autoimmune attack.
Genetic predisposition
Studies from different world regions agree that AIH depends partly on inherited variation, and the strongest signal lies in the MHC region, which is the inherited basis of the MHC predisposition above. Polymorphisms of HLA-DRB1 and HLA-DQB1 carry the major genetic risk. Genes outside the MHC contribute less; examples reported in AIH include SH2B3 (Src homology 2 adaptor protein 3), whose product regulates cytokine signalling and T-cell activation, and CARD10 (caspase recruitment domain family member 10).
Epigenetic factors
Beyond the inherited sequence, epigenetic mechanisms — changes in how genes are expressed rather than in the DNA itself — appear to contribute, mainly in the earliest stages of the disease. They act through microRNAs (miRNAs) that alter the balance between anti-inflammatory and inflammatory responses in the liver.
From tolerance loss to liver injury
Once tolerance to hepatocyte antigens is lost, the cell death is carried out mainly by CD8+ cytotoxic T cells. These cells display FasL (CD95L), a surface molecule that binds Fas (CD95) on the hepatocyte and triggers apoptosis, the programmed form of cell death. The injury does not stay confined to the hepatocytes: activated Kupffer cells, the liver’s resident macrophages, release reactive oxygen species, and hepatic stellate cells transform into myofibroblasts and deposit collagen, which is how the inflammation becomes fibrosis. This sustained injury is what the clinician meets as symptoms, abnormal blood tests and a characteristic biopsy.