Autoantibodies and Autoantigens in Autoimmune Hepatitis

Christian P. Strassburg, MD, Michael P. Manns, MD


Semin Liver Dis. 2002;22(4) 

In This Article

Autoantibodies Against Antigens of the Endoplasmic Reticulum

The ER of the cell harbors two critical enzyme families that are the main players in phase I and phase II metabolism: the CYPs and the uridine diphosphate (UDP) -glucuronosyltransferases (UGT).[53] Phase 1 metabolism leads to the oxidative modification of compounds, usually by the addition of functional groups such as hydroxylation.[54] Phase II metabolism leads to the conjugation with polar prosthetic groups such as glucuronic acid (glucuronidation).[55] In the case of the UGTs, glucuronidation leads to a water-soluble glucuronide that is targeted for renal or biliary elimination.[56] Both enzyme families are preferred targets of a B cell response in autoimmune liver diseases (Fig. 2).

Figure 2.

Autoantigen targets in autoimmune liver diseases are not tissue specific. The characterization of different target antigens has led to the definition of disease specificity of different serological markers.

Indirect immunofluorescence first led to the description of autoantibodies reactive with the proximal renal tubule and the hepatocellular cytoplasm in 1973.[57] These autoantibodies, termed LKM-1, were associated with a second form of ANA-negative AIH. Between 1988 and 1991, the 50-kD antigen of LKM-1 autoantibodies was identified as CYP 2D6.[9,10,11,12,13,14] LKM-1 autoantibodies recognize a major linear epitope between amino acids 263 and 270 of the CYP 2D6 protein.[58] These autoantibodies inhibit CYP 2D6 activity in vitro and are capable of activating liver-infiltrating T lymphocytes,[59,60] indicating the combination of B and T cell activity in the autoimmune process involved. In addition to linear epitopes,[58] LKM-1 autoantibodies have also been shown to recognize conformation-dependent epitopes.[61] However, the recognition of epitopes located between amino acids 257 and 269 appears to be a specific autoimmune reaction of AIH and is discriminatory against LKM-1 autoantibodies associated with chronic hepatitis C virus (HCV) infection.[62,63,64] CYP 2D6 has been expressed on the hepatocellular surface,[65,66] and its expression appears to be regulated by cytokines.[67]


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