Refocusing of B-cell responses following a single amino acid substitution in an antigen

Marta Dalla Chiesa, Pia M. Martensen, Cameron Simmons, Nino Porakishvili, Just Justesen, Gordon Dougan, Ivan M. Roitt, Peter J. Delves, Torben Lund

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

Intranasal immunization of BALB/c strain mice was carried out using baculovirus-derived human chorionic gonadotrophin (hCG) β-chain, together with Escherichia coli heat-labile enterotoxin. Gonadotrophin-reactive immunoglobulin A (IgA) was induced in a remote mucosal site, the lung, in addition to a systemic IgG response. The extensive sequence homology with luteinizing hormone (LH) results in the production of LH cross-reactive antibodies when holo-hCG is used as an immunogen. In contrast to wild-type hCGβ, a mutated hCGβ-chain containing an arginine to glutamic acid substitution at position 68 did not induce the production of antibodies which cross-react with LH. Furthermore, the epitopes utilized in the B-cell response to the mutated hCGβ shifted away from the immunodominant region of the parent wild-type molecule towards epitopes within the normally weakly immunogenic C terminus. This shift in epitope usage was also seen following intramuscular immunization of rabbits. Thus, a single amino acid change, which does not disrupt the overall structure of the molecule, refocuses the immune response away from a disadvantageous cross-reactive epitope region and towards a normally weakly immunogenic but antigen-unique area. Similar mutational strategies for epitope-refocusing may be applicable to other vaccine candidate molecules.

Original languageEnglish
Pages (from-to)172-178
Number of pages7
JournalImmunology
Volume103
Issue number2
DOIs
Publication statusPublished - 21 Jun 2001
Externally publishedYes

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