Galactoxylomannan-mediated immunological paralysis results from specific B cell depletion in the context of widespread immune system damage

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