Butler, Patricia Helena Gerardine; (1996) Molecular mimicry as a possible pathogenetic mechanism in primary biliary cirrhosis. Doctoral thesis (Ph.D.), University College London.

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Abstract

Data are presented to support the hypothesis that a bacterial component, through the presence of cross-reactive epitopes on M2, the highly conserved primary biliary cirrhosis (PBC) mitochondrial autoantigen, and its bacterial counterparts, may be responsible for initiating an autoimmune response in PBC through "molecular mimicry". Urinary tract infection (UTI) was more common in PBC patients than in other chronic liver disease (CLD) controls. Significant low titre anti-mitochondrial antibodies (AMA) were detected in females with a history of recurrent UTI but with no evidence of liver disease when compared to other CLD patients and normal controls. Furthermore, bacterial rough mutants were detected in the infected urine of PBC and "normal" women with UTI but not in CLD patients, despite being present in the faeces of all three groups. These findings suggest that AMA induction may be specific to UTI. Cross-reactivity was demonstrated between the M2 antigens using crude bovine mitochondrial preparations, affinity purified antibodies and western blotting (WB). Use of purified M2 antigens showed that cross-reactivity was dependent on antigen load. In addition, cross-reactivity was demonstrated between PBC sera and a range of microorganisms. Reactivity on WB was with two antigenic bands with molecular weights equivalent to two of the M2 antigenic bands. Conversely, anti-bacterial antibodies cross-reacted with the equivalent M2 antigens. The M2 autoantigen was further characterized on human cultured biliary epithelial cells (BEC). No notable cross-reactivity was demonstrated between the M2 autoantigens, only two of which were reactive with eluted PBC autoantibodies. Normal and diseased BEC were equally reactive. A database search revealed a motif in the immunodominant region of the E2 molecule of M2 with strong sequence homologies to a region of HLA DR? normally presented by other MHC class II antigens. This HLA DR? peptide was also found to resemble other protein sequences known to be associated with autoimmune disease. How these sequence similarities might initiate an autoimmune process in PBC is discussed.

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