The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/2/685/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 4, February 17, 1997 685-694

Articles

Epitope Location in the Cryptococcus neoformans Capsule Is a Determinant of Antibody Efficacy

Gabriel Nussbaum*, Wendy Cleare{ddagger}, Arturo Casadevall{ddagger}, Matthew D. Scharff*, and Philippe Valadon*

From the * Department of Cell Biology and the {ddagger} Division of Infectious Diseases, The Department of Medicine, the Albert Einstein College of Medicine, Bronx, New York 10461

Monoclonal antibodies (mAbs) to the polysaccharide capsule of Cryptococcus neoformans can prolong survival in mice. However, the properties of antibodies that mediate protection are not fully understood. The IgM mAbs 12A1 and 13F1 originated from the same B cell and differ only by somatic mutations in their variable regions; yet mAb 12A1 protects against serotype D infection, while mAb 13F1 does not. Phage peptide display libraries were used to analyze the fine specificity of these two mAbs. The selection of distinct peptide motifs from identical libraries confirmed that mAbs 12A1 and 13F1 bound to two distinct epitopes. Immunofluorescence and immunoelectron microscopy studies revealed differences in antibody localization within the capsule of serotype D strain; mAb 12A1 bound to the outer rim of the capsule resulting in an annular pattern, whereas mAb 13F1 bound throughout the capsule and had a punctate appearance. The difference in the binding pattern of mAb 12A1 and 13F1 was not observed on serotype A organisms, where both mAbs bound to the capsule with an annular fluorescence pattern. The fluorescence pattern of binding correlated with protective efficacy; mAb 13F1 prolonged survival of mice infected with the J11 serotype A strain (annular fluorescence), but not serotype D strains (punctate pattern). Annular binding, but not punctate binding, was associated with increased opsonic efficacy for phagocytosis of C. neoformans by J774.16 macrophage-like cells. The correlation between capsular binding pattern, opsonic activity, and ability to prolong survival suggests that the efficacy of anticryptococcal antibodies is dependent upon where they bind in the polysaccharide capsule.

Address correspondence to Dr. Matthew D. Scharff, Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461.

1Abbreviations used in this paper: BPB, biopanning buffer; GXM, glucuronoxylomannan; GXM-TT, GXM conjugated to tetanus toxoid; IEM, immunoelectron microscopy; TU, transducing units.


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