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Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: the molecule versus the mimic

Record type: Article

The 2-oxo-acid dehydrogenase complexes and, in particular, the E2 component of the pyruvate dehydrogenase complex (PDC) are the target of antimitochondrial antibodies (AMA). More than 95% of primary biliary cirrhosis (PBC) patients have detectable levels of autoantibodies to PDC-E2 and in general these react with a region of the molecule that contains the prosthetic group lipoic acid (LA). LA is vital to the function of the enzyme, although there is conflicting evidence as to whether its presence is required for PDC-E2 recognition by AMA. Some, but not all, monoclonal antibodies (mAbs) to PDC-E2 produce an intense staining pattern at the apical surface of bile duct epithelial cells (BEC) in patients with PBC, and it has been argued that the molecule at the apical surface of PBC bile duct cells is a modified form of PDC-E2 or a cross-reactive molecule, acting as a molecular mimic. Herein, we characterize the epitopes recognized by 4 anti-PDC-E2 mAbs that give apical staining patterns (3 mouse and 1 human). In particular, by using a combination of recombinant antigens, competitive inhibition assays, and a unique peptide-on-bead assay, we determined that these apically staining mAbs recognize 3 or 4 distinct epitopes on PDC-E2. More importantly, this suggests that a portion spanning the entire inner lipoyl domain of PDC-E2 can be found at the BEC apical surface. In addition, competition assays with patient sera and a PDC-E2-specific mAb showed significant epitope overlap with only 1 of the 3 mouse mAbs and showed a differential response to the peptide bound to beads. These findings further highlight the heterogeneous response of patient autoantibodies to the inner lipoyl domain of PDC-E2.

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Citation

Migliaccio, C., Van de Water, J., Ansari, A .A., Kaplan, M. M., Coppel, R. L., Lam, K. S., Thompson, R. K., Stevenson, F. and Gershwin, M. E. (2001) Heterogeneous response of antimitochondrial autoantibodies and bile duct apical staining monoclonal antibodies to pyruvate dehydrogenase complex E2: the molecule versus the mimic Hepatology, 33, (4), pp. 792-801. (doi:10.1053/jhep.2001.23783).

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Published date: April 2001

Identifiers

Local EPrints ID: 157827
URI: http://eprints.soton.ac.uk/id/eprint/157827
ISSN: 0270-9139
PURE UUID: 928f7931-9ef2-4b58-83bb-b8683db187a6

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Date deposited: 06 Jul 2010 13:39
Last modified: 18 Jul 2017 12:40

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Contributors

Author: C. Migliaccio
Author: J. Van de Water
Author: A .A. Ansari
Author: M. M. Kaplan
Author: R. L. Coppel
Author: K. S. Lam
Author: R. K. Thompson
Author: F. Stevenson
Author: M. E. Gershwin

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