Autoantibodies and Autoantigens in Autoimmune Hepatitis

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

Disclosures

Semin Liver Dis. 2002;22(4) 

In This Article

Microsomal Antibodies and Disease Associations

The characterization of autoantibodies directed against CYPs and UGTs has led to the definition of specificities that span a number of immune-mediated diseases (see Fig. 2; Table 3 ). These include AIH, drug-induced hepatitis,[68,69,70] APS-1,[26,71] and chronic HCV and hepatitis D virus (HDV).[72]

LKM autoantibodies against CYP 1A2 and CYP 2A6 are found in patients with APS-1 and hepatic involvement.[24,25,73] Anti-CYP 2A6 autoantibodies also occur in HCV infection.[62,74] LM autoantibodies, which are characterized by an immunofluorescence pattern selectively staining the hepatocellular cytoplasm but not the kidney, have been found to be directed against CYP 1A2.[71,75,76] These autoantibodies are also found in APS-1 syndrome with hepatic involvement and occur in dihydralazine-induced hepatitis.[24,77] A second type of LKM autoantibodies, LKM-2, is directed against CYP 2C9 and is induced in ticrynafen-associated hepatitis.[68,78] A third group of LKM autoantibodies, LKM-3, was identified in 6 to 10% of patients with chronic HDV infection by Crivelli et al.[79] These autoantibodies are directed against family 1 UDP-glucuronosyltransferases (UGTIA),[80,81] which are also a superfamily of drug-metabolizing proteins located in the ER.[55,82] LKM-3 autoantibodies have been identified in HDV infection and also in AIH type 2 patients.[80,81] They can also occur in LKM-1-negative and ANA-negative AIH[81] and thus may become the only serological marker of AIH.

A small percentage of patients treated with therapeutic drugs can develop severe hepatitis, which is characterized by lymphocytic liver infiltrations and autoantibodies directed against hepatic proteins. It is believed that drug-metabolizing enzymes, mainly CYPs, create reactive metabolites, which in turn modify either the metabolizing CYP enzyme itself or other hepatic proteins.[83,84,85] In susceptible patients, these modified proteins induce an immune response resulting in severe drug-induced hepatitis.[86] Modified proteins preferentially include CYPs, which are often targets for autoantibodies. As typical examples, tienilic acid-induced hepatitis,[87] dihydralazine hepatitis,[77] halothane hepatitis,[88] and anticonvulsant-induced hepatitis[89] have been characterized. It is debated whether alcoholic liver disease is caused in part by an autoimmune reaction against hepatic proteins directed against both acetaldehyde- and hydroxyethyl-modified hepatic proteins.[90,91] It has been suggested that metabolism of ethanol by CYP 2E1 generates hydroxyethyl radicals that can represent targets of autoimmunity.[91]

LKM autoantibodies have also been identified to react with yet-unidentified proteins. These include antigens with molecular weights of 35 kD, 57 kD, 59 kD, and 70 kD. These autoantibodies are predominantly found in AIH, HCV infection, and halothane hepatitis.[92]

LKM autoantibodies are visualized by indirect immunofluorescence on rodent cryostat sections. Subclassification is achieved by enzyme-linked immunosorbent assay (ELISA) and Western blot, preferably using recombinant antigens.

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