Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Adams, C. L., Macleod, M. K.L., Milner-White, E. J., Aitken, R., Garside, P. and Stott, D.I. (2003) Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation. Immunology, 108(3), pp. 274-287. (doi:10.1046/j.1365-2567.2003.01583.x) (PMID:12603593)

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Abstract

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4+ T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system in vivo. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation.

Item Type:Articles
Additional Information:© Blackwell. The definitive version is available at www.blackwell-synergy.com
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Stott, Professor David and Aitken, Professor Robert and Garside, Professor Paul and Milner-White, Professor E and Macleod, Dr Megan
Authors: Adams, C. L., Macleod, M. K.L., Milner-White, E. J., Aitken, R., Garside, P., and Stott, D.I.
Subjects:Q Science > QR Microbiology > QR180 Immunology
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Immunology
Publisher:Blackwell
ISSN:0019-2805
Published Online:25 February 2006
Copyright Holders:Copyright © 2003 Blackwell
First Published:First published in Immunology 108(3):274-287
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher.

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