Galactoxylomannan-mediated immunological paralysis results from specific B cell depletion in the context of widespread immune system damage
- Publication date
- Publisher
Abstract
16 p. : il.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 (GXM) and galactoxylomannan
(GalXM) elicit little or no antibody 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 antibody-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 antigen. Additionally, immunization
with GalXM in either complete or incomplete Freund's adjuvant was associated with spleen
enlargement in Balb/c mice. Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End
Labeling (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
antibody 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 pro-apoptotic properties in the context of widespread dysregulation of immune function