Bogdanos, D.; (2005) Molecular mimicry in primary biliary cirrhosis and other hepatic and extra-hepatic diseases. Doctoral thesis , University of London.

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Abstract

This Thesis investigates the concept that molecular mimicry may be instrumental to the appearance and/or maintenance of liver autoimmunity, with a main focus on primary biliary cirrhosis (PBC). The first part of the study concentrates on the investigation of immunological cross-reactivity between pyruvate dehydrogenase complex E2 (PDC-E2)212-226, the immunodominant mitochondrial autoepitope in PBC and microbial mimics. Several bacterial and viral sequences were identified that share extensive homology with PDC-E2212-226 and while some from mycobacteria, lactobacillus and E. coli, acted as target of cross-reactivity, similarly good mimicking sequences from other micro-organisms were unreactive. The possible bearing on the mechanism of the disease of this selective cross-reactivity is discussed. Next is the identification of cross-reactive immune responses between hepatitis C virus (HCV) polyprotein and cytochrome P450IID6 (CYP2D6)252-27i, the major autoepitope of anti-liver kidney microsomal type-1 antibody (LKM1), the serological hallmark of autoimmune hepatitis type-2. Viral/self cross-reactivity was documented only in those patients possessing the HLA B51 allele. The evolution of immunological cross-reactivity was investigated over a 10-year period in a girl who developed primary and secondary LKM1 response following HCV infection resulting in a florid autoimmune hepatitis 9 years later. A study in a cohort of subjects vaccinated against hepatitis B provided the opportunity to document the appearance of cross-reactivity between viral sequences and mimics on myelin antigens. The findings of the present Thesis demonstrate that disease-specific microbial/self cross-reactive responses do occur and may be of pathogenic significance.

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