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Hepatology ; 57(4): 1498-508, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23184636

ABSTRACT

UNLABELLED: Antimitochondrial antibodies (AMAs) directed against the lipoyl domain of the E2 subunit of pyruvate dehydrogenase (PDC-E2) are detected in 95% of patients with primary biliary cirrhosis (PBC) and are present before the onset of clinical disease. The recent demonstration that AMAs 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 immunoglobulin M (IgM) and using sera from a large cohort of PBC patients and controls (n = 516), we examined in detail sera reactivity against either 6,8-bis(acetylthio) octanoic acid (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 enzyme-linked immunosorbent assay (ELISA); SAc conjugate and rPDC-E2-specific affinity-purified antibodies were also examined for antigen specificity, isotype, and crossreactivity. 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, crossreactivity, 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 than to rPDC-E2 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. CONCLUSION: 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.


Subject(s)
Antibodies, Anti-Idiotypic/immunology , Liver Cirrhosis, Biliary/etiology , Liver Cirrhosis, Biliary/immunology , Mitochondria/immunology , Xenobiotics/adverse effects , Antibody Specificity , Autoantigens/immunology , Case-Control Studies , Cholangitis, Sclerosing/blood , Cholangitis, Sclerosing/immunology , Dihydrolipoyllysine-Residue Acetyltransferase/immunology , Hepatitis, Autoimmune/blood , Hepatitis, Autoimmune/immunology , Humans , Immunoglobulin M/blood , Liver Cirrhosis, Biliary/blood , Mitochondrial Proteins/immunology , Recombinant Proteins/immunology , Serum Albumin, Bovine/immunology
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