Regulation of Homeostatic Intestinal IgA Responses by the TNF Family

• Main Author: McCarthy, Douglas
• Other Authors: Gommerman, Jennifer Lynn
• Language: en_ca
• Published: 2010
• Subjects: Intestinal immunology; Commensal flora; IgA; TNF superfamily; BAFF; Lymphotoxin; IgA nephropathy; 0982; 0410
• Online Access: http://hdl.handle.net/1807/30044

The mammalian immune system has developed diverse strategies to protect the gastrointestinal tract, as this tissue locale represents a huge absorptive surface and is susceptible to microbial breach. Paradoxically, one key aspect of this protective strategy is the maintenance of selected commensal microorganisms. These commensals serve essential roles in digestion, interfere with pathogenic microbial invasion and stimulate development of the host immune system. Therefore, immune responses which deplete these commensal populations are detrimental to the host. One effective intestinal immune response which selectively promotes the survival of commensals is production of antibodies of the IgA isotype which bind to bacteria without triggering inflammatory cytokines. Proteins of the tumor necrosis factor (TNF) family such as Lymphotoxin and BAFF contribute to the induction of IgA responses. Lymphotoxin is required for generation and organization of most organized lymphoid tissues, where B cell differentiation occurs, while BAFF is necessary for B cell survival and induces B cells to produce IgA. In this thesis, I describe work I have done in examining the roles of the TNF family members Lymphotoxin, BAFF and two related TNF family member cytokines, LIGHT and APRIL, in the regulation of IgA production in mice and in humans. Specifically, LIGHT over-expression drives immense production of IgA, leading to renal deposition of immune complexes in mice. Similar to LIGHT, BAFF over-expression drives increases in IgA production in the intestine, however I have shown that the effects of the BAFF pathway on IgA hyper-production are independent of LIGHT activity. Secondly, examining the phenotype of BAFF-over-expressing mice, I have shown that this phenotype resembles human IgA nephropathy (IgAN) and is dependent on intestinal commensals. Finally, I have described a lymphotoxin-dependent chemokine system in the intestinal lamina propria that could be responsible for organizing cells for the development of IgA responses in this mucosal site.