The influence of IgA on B Cell Homeostasis

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DESCRIPTION (provided by applicant): Mucosal tissue, the first line of defense against the majority of infectious agents, contains large amounts of IgA antibody, which serves to rapidly neutralize toxins and pathogens, while preventing inflammation. Perturbations in IgA levels can thus be expected to severely affect immune defenses and homeostasis at mucosal tissues. Surprisingly, we have found that IgA deficient mice (IgA-/- mice) specifically fail to mount class-switched antibody responses to polysaccharide vaccines but respond in a normal fashion to protein vaccines. Perhaps related to this, there is a dramatic reduction in the numbers of mucosal B cells in IgA-/- mice and the levels of peritoneal B1-a cells are also decreased. Thus, we hypothesize that IgA expression is critical for the proper trafficking and retention of B cells in mucosal tissues. We will investigate the influence of IgA on B cell homeostasis with a particular focus on B1-a cells by 1) determining the specific nature of the mucosal B cell defect in IgA-/- mice and 2) establishing the mechanism by which IgA influences trafficking and maintenance of mucosal B cells. These studies will advance our understanding of the dynamic interactions between IgA, B cells, and the environment, a relatively unexplored area with significant relevance to human health. RELEVANCE: IgA deficiency is the most frequent form of primary immunodeficiency in humans. This proposal seeks to determine the reason for recurrent respiratory infections and poor responsiveness to polysaccharide vaccines that is observed in many of these patients. By exploiting a unique IgA immunodeficient mouse model, our results will ultimately allow design of new therapeutics and adjuvants to improve the efficacy of vaccines in this population.