A fundamental goal in modern immunology is to understand the factors that contribute to the homeostatic balance between commensal microbes and the host immune system. Although a great deal has been done to understand the role of commensals in shaping T cell responses, a large gap remains in understanding how commensals impact B lymphocyte development and associated antibody diversification. Continued existence of this gap is an important problem because until filled, our understanding of regulatory principles underlying humoral immune fitness as well as vulnerability to allergic and inflammatory diseases will remain incomplete. The overall objective of this proposal is to determine how commensal microbes affect primary B cell development and pre-immune immunoglobulin (Ig) diversification. Based on recent findings from the applicant, the central hypothesis is that commensal microbes provide inputs through host sensory instruments to regulate early B cell developmental activities in the host gut mucosa, thus empowering luminal antigens with the capacity to influence the primary Ig repertoire locally. This is consistent with observations that several other species, such as rabbits and sheep, utilize the intestine as a significant site for primary Ig diversification early in post-natal life. The rationale for the proosed research is that, once accomplished, the field will move vertically towards a greater understanding of the role of commensals in immune homeostasis and will open the door to further exploration of modifiable environmental factors that could be targeted, resulting in new and innovative approaches to influence a variety of health issues relevant to antibody production. Using both new as well as established technologies, this proposal's three aims will build upon the applicant's recent work. With the deployment of ex vivo co-culture as well as established in vivo labeling methods, aim 1 will test the notion that commensals influence both gut-resident as well as bone marrow support systems to stimulate early B lineage cell development and is expected to identify the gut-resident support mechanisms enabling early B lineage cells to survive and respond to microbial input. With the use of germ-free and gnotobiotic facilities, aim 2 will determine the extent to which microbe composition has specific effects to shape the primary Ig repertoire. With sophisticated genetically modified mouse models as well as powerful imaging technologies, aim 3 will evaluate the degree to which luminal antigens gain access to the intestinal lamina propria and interact with freshly-produced, cell-bound Ig in young mice. The proposed research is significant for the following three reasons - first, it promises to provide a more complete picture of the general principles of host:microbe interactions in immune regulation; second, it will be a first step to identify the extent to which primary Ig repertoires can be influenced by modifiable environmental exposures early in life; and third, it provides an essential component to establish a platform for testing future hypotheses regarding the effect of specific commensal microbe ecologies on downstream antibody responses to pathogens, allergens and vaccines.
The proposed research is relevant to public health because the discovery of the role of commensal microbes on cells that generate antibodies is ultimately expected to increase understanding of health issues in which antibodies play a key role - such as allergy, autoimmunity and vaccine development. Thus, the proposed research is relevant to the part of the NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of human disability.
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