Molecular basis for immunoglobulin M specificity to epitopes in Cryptococcus neoformans polysaccharide that elicit protective and nonprotective antibodies

A. Nakouzi, P. Valadon, Joshua D. Nosanchuk, N. Green, A. Casadevall

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The protective efficacy of antibodies (Abs) to Cryptococcus neoformans glucuronoxylomannan (GXM) is dependent on Ab fine specificity. Two clonally related immunoglobulin M monoclonal Abs (MAbs) (12A1 and 13F1) differ in fine specificity and protective efficacy, presumably due to variable (V)-region sequence differences resulting from somatic mutations. MAb 12A1 is protective and produces annular immunofluorescence (IF) on serotype D C. neoformans, while MAb 13F1 is not protective and produces punctate IF. To determine the Ab molecular determinants responsible for the IF pattern, site-directed mutagenesis of the MAb 12A1 heavy-chain V region (VH) was followed by serological and functional studies of the various mutants. Changing two selected amino acids in the 12A1 VH binding cavity to the corresponding residues in the 13F1 VH altered the IF pattern from annular to punctate, reduced opsonic efficacy, and abolished recognition by an antiidiotypic Ab. Analysis of the binding of the various mutants to peptide mimetics revealed that different amino acids were responsible for GXM binding and peptide specificity. The results suggest that V-region motifs associated with annular binding and opsonic activity may be predictive of Ab efficacy against C. neoformans. This has important implications for immunotherapy and vaccine design that are reinforced by the finding that GXM and peptide reactivities are determined by different amino acid residues.

Original languageEnglish (US)
Pages (from-to)3398-3409
Number of pages12
JournalInfection and Immunity
Volume69
Issue number5
DOIs
StatePublished - 2001

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Cryptococcus neoformans
Fluorescent Antibody Technique
Polysaccharides
Immunoglobulin M
Epitopes
Antibodies
Amino Acids
Peptides
Site-Directed Mutagenesis
Immunotherapy
Vaccines
Monoclonal Antibodies
Mutation
glucuronoxylomannan

ASJC Scopus subject areas

  • Immunology

Cite this

Molecular basis for immunoglobulin M specificity to epitopes in Cryptococcus neoformans polysaccharide that elicit protective and nonprotective antibodies. / Nakouzi, A.; Valadon, P.; Nosanchuk, Joshua D.; Green, N.; Casadevall, A.

In: Infection and Immunity, Vol. 69, No. 5, 2001, p. 3398-3409.

Research output: Contribution to journalArticle

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