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* Department of Microbiology and Immunology of the Albert Einstein College of Medicine, Bronx, NY 10461; and
University of Brasilia, Brasilia, Brazil
The mechanisms responsible for polysaccharide-induced immunological paralysis have remained unexplained almost a century after this phenomenon was first described. Cryptococcus neoformans capsular polysaccharides glucuronoxylomannan and galactoxylomannan (GalXM) elicit little or no Ab responses. This study investigates the immunological and biological effects of GalXM in mice. GalXM immunization elicits a state of immunological paralysis in mice characterized by the disappearance of Ab-producing cells in the spleen. Immunological paralysis and lack of immunogenicity could not be overcome by immunization with GalXM conjugated to a protein carrier, Bacillus anthracis protective Ag. Additionally, immunization with GalXM in either complete or IFA was associated with spleen enlargement in BALB/c mice. TUNEL and flow cytometry revealed widespread apoptosis in the spleen after GalXM administration. Administration of a cocktail of caspase-3 inhibitor Z-DEVD-FMK and general caspase inhibitor Z-VAD-FMK or Fas-deficient mice abrogated the complete disappearance of Ab-producing cells. Analysis of spleen cytokine expression in response to GalXM systemic injection revealed that GalXM down-regulated the production of inflammatory cytokines. Hence, we conclude that GalXM-induced immune paralysis is a result of specific B cell depletion mediated by its proapoptotic properties in the context of widespread dysregulation of immune function.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI33774, AI33142, and HL59842-01 (to A.C.). M.D. was supported by National Cancer Institute/National Institutes of Health Training Grant 2T32CA009173-31. The Complex Carbohydrate Research Center is supported by the Department of Energy Center for Plant and Microbial Complex Carbohydrates, DE-FG09-93ER-20097. The Wadsworth Laboratories is supported by Northeast Biodefense Center under Grant 2U54AI057158-06. The Albert Einstein College of Medicine Flow Cytometry Core Facility was supported by Grant P30CA013330.
2 Parts of this work were presented at the 106th General Meeting of the American Society for Microbiology, Orlando, FL, May 2006 (Abstr. F-013). The data in this paper are from a thesis to be submitted by Magdia De Jesus in partial fulfillment of the requirements for the Ph.D. degree in the Sue Golding Graduate Division of Medical Science, Albert Einstein College of Medicine, Yeshiva University, Bronx, NY.
3 Address correspondence and reprint requests to Dr. Arturo Casadevall, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer 411, Bronx, NY 10461. E-mail address: casadeva{at}aecom.yu.edu
4 Abbreviations used in this paper: GXM, glucuronoxylomannan; GalXM, galactoxylomannan; IFA, incomplete Freund’s adjuvant; PA, protective Ag; scFv, single-chain variable fragment.
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