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.
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.
| Esteves, Pedro J; Abrantes, Joana; Baldauf, Hanna-Mari et al. (2018) The wide utility of rabbits as models of human diseases. Exp Mol Med 50:66 |
| Paynich, Mallory L; Jones-Burrage, Sara E; Knight, Katherine L (2017) Exopolysaccharide from Bacillus subtilis Induces Anti-Inflammatory M2 Macrophages That Prevent T Cell-Mediated Disease. J Immunol 198:2689-2698 |
| Lanning, Dennis K; Esteves, Pedro J; Knight, Katherine L (2017) The remnant of the European rabbit (Oryctolagus cuniculus) IgD gene. PLoS One 12:e0182029 |
| von Eichel-Streiber, Alice; Paik, Wonbeom; Knight, Katherine et al. (2016) Induction of antitoxin responses in Clostridium-difficile-infected patients compared to healthy blood donors. Anaerobe 41:91-103 |
| Semenyuk, Ekaterina G; Poroyko, Valeriy A; Johnston, Pehga F et al. (2015) Analysis of Bacterial Communities during Clostridium difficile Infection in the Mouse. Infect Immun 83:4383-91 |
| Semenyuk, Ekaterina G; Laning, Michelle L; Foley, Jennifer et al. (2014) Spore formation and toxin production in Clostridium difficile biofilms. PLoS One 9:e87757 |
| Johnston, Pehga F; Gerding, Dale N; Knight, Katherine L (2014) Protection from Clostridium difficile infection in CD4 T Cell- and polymeric immunoglobulin receptor-deficient mice. Infect Immun 82:522-31 |
| 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 |
| Jones, Sara E; Paynich, Mallory L; Kearns, Daniel B et al. (2014) Protection from intestinal inflammation by bacterial exopolysaccharides. J Immunol 192:4813-20 |
| Yeramilli, Venkata A; Knight, Katherine L (2013) Development of CD27+ marginal zone B cells requires GALT. Eur J Immunol 43:1484-8 |
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