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Infection and Immunity, May 2001, p. 3398-3409, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3398-3409.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Molecular Basis for Immunoglobulin M Specificity to Epitopes in Cryptococcus neoformans Polysaccharide That Elicit Protective and Nonprotective Antibodies

Antonio Nakouzi,1 Philippe Valadon,2 Joshua Nosanchuk,1 Nancy Green,3 and Arturo Casadevall1,4,*

Division of Infectious Diseases, Department of Medicine,1 and Departments of Pediatrics3 and Microbiology and Immunology,4 Albert Einstein College of Medicine, Bronx, New York 10461, and Sidney Kimmel Cancer Center, San Diego, California 921212

Received 22 December 2000/Returned for modification 24 January 2001/Accepted 7 February 2001

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 anti-idiotypic 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.

* Corresponding author. Mailing address: Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3665. Fax: (718) 430-8701. E-mail: casadeva{at}aecom.yu.edu.

Infection and Immunity, May 2001, p. 3398-3409, Vol. 69, No. 5
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.5.3398-3409.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Frases, S., Nimrichter, L., Viana, N. B., Nakouzi, A., Casadevall, A. (2008). Cryptococcus neoformans Capsular Polysaccharide and Exopolysaccharide Fractions Manifest Physical, Chemical, and Antigenic Differences. Eukaryot Cell 7: 319-327 [Abstract] [Full Text]  
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