The intestinal commensal microbiota is required for development of lymphoid tissues and mucosal immunity in vertebrates. However, little is known of the mechanism by which these processes occur. Previous work in rabbits has demonstrated that the intestinal commensal microbiota is required for expansion of B cells and somatic diversification of Ig genes during development of the preimmune antibody repertoire, both of which occur in gut-associated lymphoid tissues (GALT). These processes occur within a few days after birth in an antigen- and T cell-independent manner, and surprisingly, they require activation of complement. We hypothesize a model for GALT development in which B cells enter GALT from the bone marrow soon after birth and migrate to the follicle-associated epithelium (FAE) and interact with C'-coated bacteria from the lumen. These complexes are then delivered to FDCs which provide stimulatory signals for B cell activation and upregulation of AID expression;within a few weeks after birth, essentially all Ig genes are somatically diversified, thereby providing the rabbits with a diverse antibody repertoire. The goal of this grant is to test this model of GALT development.
In Aim 1 we will use soluble chemokine receptors to inhibit chemokine-driven migration and determine how the migration of B cells is altered;
in Aim 2, we will use sterile GALT explants and TLR and NLR agonists and antagonists to determine the contribution of TLR and NLR ligands and IgM-binding bacterial superantigen-like molecules to B cell proliferation and Ig gene diversification;we will also use sterile explants of GALT as well as an in vitro FDC:B cell culture system to determine how complement activation contributes to GALT development.
In Aim 3, we will search in gnotobiotic CD4-/- mice for GALT-like B cells that proliferate in an antigen and T-cell independent manner and undergo somatic diversification of the Ig genes. These experiments are important because they will begin to determine the mechanism by which commensal bacteria and complement contribute to development of mucosal lymphoid tissues and ultimately to human health and disease such as allergy and inflammatory bowel disease.

Public Health Relevance

The goal of this proposal is to determine the mechanism by which intestinal commensal bacteria promote development of gut-associated lymphoid tissues. These studies will provide insight into the origin of bacteria-induced gastrointestinal diseases such as inflammatory bowel disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050260-11
Application #
8516433
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Rothermel, Annette L
Project Start
2001-08-05
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
11
Fiscal Year
2013
Total Cost
$354,850
Indirect Cost
$119,850
Name
Loyola University Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153
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Zhai, Shi-Kang; Volgina, Veronica V; Sethupathi, Periannan et al. (2014) Chemokine-mediated B cell trafficking during early rabbit GALT development. J Immunol 193:5951-9
Yeramilli, Venkata A; Knight, Katherine L (2013) Development of CD27+ marginal zone B cells requires GALT. Eur J Immunol 43:1484-8
Yeramilli, Venkata A; Knight, Katherine L (2011) Somatically diversified and proliferating transitional B cells: implications for peripheral B cell homeostasis. J Immunol 186:6437-44
Siewe, Basile T; Kalis, Susan L; Esteves, Pedro J et al. (2010) A novel functional rabbit IL-7 isoform. Dev Comp Immunol 34:828-36
Severson, Kari M; Mallozzi, Michael; Driks, Adam et al. (2010) B cell development in GALT: role of bacterial superantigen-like molecules. J Immunol 184:6782-9
Yeramilli, Venkata A; Knight, Katherine L (2010) Requirement for BAFF and APRIL during B cell development in GALT. J Immunol 184:5527-36
Severson, Kari M; Mallozzi, Michael; Bozue, Joel et al. (2009) Roles of the Bacillus anthracis spore protein ExsK in exosporium maturation and germination. J Bacteriol 191:7587-96
Kalis, Susan L; Zhai, Shi-Kang; Yam, Pi-Chen et al. (2007) Suppression of B lymphopoiesis at a lymphoid progenitor stage in adult rabbits. Int Immunol 19:801-11

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