Microbial Mannan As A Cause Of Phagocyte Dysfunction In Crohn's Disease

Crohn's disease (CD) is a granulomatous condition that is mimicked by rare inherited disorders of phagocyte function and has clinical features compatible with an underlying impaired' defence against the gut microbiota. Crohn's'disease patients commonly have circulating antibodies (ASCA) against a mannan present in baker's yeast (Saccharomyces cerevisiae). I have investigated the possibility that S.cerevisiae mam?-ans may induce defects in phagocyte function. Saccharomyces cerevisiae mannan is shown to inhibit several of the functions of normal human peripheral blood neutrophils, monocytes and monocyte-derived macrophages including chemiluminescence and killing of phagocytosed bacteria. CD mucosa-associated E. coli isolates, that are less readily killed following internalization within adherent monocytes than a control ATCC259222 E. coli strain, undergo net replication inside adherent monocytes in the presence of S.cerevisiae mannan. S.cerevisiae mannan similarly enhanced survival of S. aureus within adherent monocytes. The epitope for ASCA is a mannose al-3 mannose disaccharide that binds snowdrop (Galanthus nivalis) lectin (GNA). A range of putative Crohn's diseaseassociated organisms was screened by GNA lectin blotting. The ASCA epitope was expressed by Mycobacterium avium paratuberculosis but not by M tuberculosis or E. coli. Crohn's disease may arise in part as a consequence of the suppression of mucosal phagocyte function by shed microbial mannans.EThOS - Electronic Theses Online ServiceGBUnited Kingdo