The University of Southampton
University of Southampton Institutional Repository

Immunogenetic analysis reveals that epitope shifting occurs during B-cell affinity maturation in primary biliary cirrhosis

Record type: Article

Primary biliary cirrhosis (PBC) is a liver disease characterized by serum autoantibodies against the pyruvate dehydrogenase complex (PDC) located in the inner mitochondrial membrane. The predominant target in PDC has previously been localized to the inner lipoyl domain (ILD) of the E2 subunit. The etiology of PBC is unknown, although molecular mimicry with bacterial PDC has been proposed. Here, we have investigated the etiology of PBC and nature of the autoimmune response by analyzing the structure of a human monoclonal antibody with ILD specificity. Mutants of the monoclonal antibody, which was originally isolated from a patient with PBC, were expressed as Fab by phage display, and tested for reactivity against recombinant domains of the E2 subunit. Fab in which the VH-encoded portions were reverted to germline lost reactivity against the ILD alone, but recognized a different epitope in a didomain construct encompassing the ILD, hinge region and E1/E3 binding domain. The complete VH and VLgermline revertant was unreactive with the human ILD and didomain, the Escherichia coli didomain, and whole PDC. We hypothesize that the IgM on the surface of the naïve B-cell first recognizes an as yet unidentified antigen, and that accumulation of somatic mutations results in an intermolecular epitope shift directed towards an epitope involving the E1/E3 binding domain. Further mutations result in the specificity being redirected to the ILD. These findings also suggest that bacterial molecular mimicry is not involved in initiating disease.

Full text not available from this repository.

Citation

Potter, Kathleen N., Thomson, Richard K., Hamblin, Angela, Richards, Susan D., Lindsay, J. Gordon and Stevenson, Freda K. (2001) Immunogenetic analysis reveals that epitope shifting occurs during B-cell affinity maturation in primary biliary cirrhosis Journal of Molecular Biology, 306, (1), pp. 37-46. (doi:10.1006/jmbi.2000.4210).

More information

Published date: 2001
Keywords: autoimmune disease, autoantibodies, germline revertant, V-genes, epitope spreading

Identifiers

Local EPrints ID: 26535
URI: http://eprints.soton.ac.uk/id/eprint/26535
ISSN: 0022-2836
PURE UUID: 31a2bb78-3faf-45d3-be65-89c3a9c57974

Catalogue record

Date deposited: 24 Apr 2006
Last modified: 17 Jul 2017 16:07

Export record

Altmetrics

Contributors

Author: Richard K. Thomson
Author: Angela Hamblin
Author: Susan D. Richards
Author: J. Gordon Lindsay

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×