Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis

Abstract

Antimitochondrial antibodies (AMA) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with PBC and are present before onset of clinical disease. The recent demonstration that AMA recognize xenobiotic modified PDC-E2 with higher titers than native PDC-E2, raises the possibility that the earliest events involved in loss of tolerance are related to xenobiotic modification. We hypothesized that reactivity to such xenobiotics would be predominantly IgM and using sera from a large cohort of PBC patients and controls (n=516), we examined in detail sera reactivity against either SAc-conjugated bovine serum albumin (BSA), recombinant PDC-E2 (rPDC-E2) or BSA alone. Further, we also defined the relative specificity to the SAc moiety using inhibition ELISA; SAc conjugate and rPDC-E2 specific affinity purified antibodies were also examined for antigen specificity, isotype and cross-reactivity. Reactivity to SAc conjugates is predominantly IgM; such reactivity reflects a footprint of previous xenobiotic exposure. Indeed, this observation is supported by both direct binding, cross reactivity, and inhibition studies. In both early and late stage PBC, the predominant Ig isotype to SAc is IgM, with titers higher with advanced stage disease. We also note that there was a higher level of IgM reactivity to SAc in early stage versus late stage PBC. Interestingly, this finding is particularly significant in light of the structural similarity between SAc and the reduced form of lipoic acid, a step which is similar to the normal physiological oxidation of lipoic acid. We submit that specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e. by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host.

Innate immunity drives xenobiotic-induced murine autoimmune cholangitis

“…PBC exhibits several features characteristic of an autoimmune disease including the presence of the hallmark AMAs directed against the PDC-E2, autoreactive T cells in portal tracts and the specific immune targeting of cholangiocytes [45][46][47][48]. Thus PBC is an autoimmune disease and immunosuppressive agents, including corticosteroids, azathioprine, cyclosporin and methotrexate, should theoretically be successful to treat PBC; however, a clear benefit has not been demonstrated to date [4].…”

Versatile characterization of glycosylation modification in CTLA4-Ig fusion proteins by liquid chromatography-mass spectrometry

“…Compared to other biosimilar therapeutics, mAb and antibody-derivative biosimilars guidance has experienced delays. 6 The main reason is that antibody-derivatives are glycoproteins, which are large, complicated and heterogeneous proteins with the complex post-translational modifications (PTMs). Researchers have shown that regulatory approval of biosimilars of mAb and antibody-derivative is subjected to specific, science-based guidelines.…”

The Pathogenesis of Autoimmune Liver Disease

“…Some bacteria such as Escherichia coli have been proposed to cross-react with mitochondrial proteins, and this may explain why recurrent urinary infections are more commonly seen in PBC patients than in healthy controls [17] . Furthermore, the role of xenobiotics in PBC is thought to be important; the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) can be replaced by a chemical xenobiotic mimic, which experimentally can be shown to be sufficient to break immunological self-tolerance [18] . Potential xenobiotics are speculated to be found in substances patients are commonly exposed to, including nail varnish, hair dye and cleaning chemicals [16] .…”