Antimitochondrial antibody heterogeneity and the xenobiotic etiology of primary biliary cirrhosis.

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.

• Authors: Richy C Y Chen, Phornnop Naiyanetr, Shang-An Shu, Jinjun Wang, Guo-Xiang Yang, Thomas P Kenny, Kathryn C Guggenheim, Jeffrey D Butler, Christopher Bowlus, Mi-Hua Tao, Mark J Kurth, Aftab A Ansari, Marshall Kaplan, Ross L Coppel, Ana Lleo, M Eric Gershwin, Patrick S C Leung
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 57 Issue 4 Pg. 1498-508 (Apr 2013) ISSN: 1527-3350 [Electronic] United States
• PMID: 23184636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2012 American Association for the Study of Liver Diseases.

Chemical References

• Antibodies, Anti-Idiotypic
• Autoantigens
• Immunoglobulin M
• Mitochondrial Proteins
• Recombinant Proteins
• Xenobiotics
• Serum Albumin, Bovine
• DLAT protein, human
• Dihydrolipoyllysine-Residue Acetyltransferase

Topics

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