The goal of this project is to """"""""define factors contributing to the formation and regulation of germinal centers (GC)."""""""" GCs develop in lymphoid follicles during T cell-dependent humoral responses and are the birthplace of memory B cells. Dr. Clark and his colleagues will investigate molecular mechanisms regulating a key antigen presenting cell (APC) in the germinal center: the follicular dendritic cell (FDC). They have isolated a cDNA encoding a novel member of the tumor necrosis factor (TNF) receptor (TNFR) family, they call FDC receptor 1 or FDCR1. They propose to define the role of FDCR1 in the regulation of GC formation and humoral responses and to identify and characterize FDC-associated genes which regulate GC B cells.
The Specific Aims are: 1) To test the hypothesis that FDCR1 plays a role in vivo in regulating the development and lifespan of germinal centers and antigen-specific B cells. They have isolated the mouse Fdcr1 gene, disrupted one copy in ES cells and begun preparing FDCR1-/- mice. They will examine whether FDCR1-/- mice compared to FDCR1+/+ mice have deficient T cell-dependent humoral responses including deficient GC formation, IgG antibody respones and long-lived B cells; 2) To test the hypothesis that FDCR1 functions as a soluble cytokine to alter expression of TNFR/TNF family members and cell fate. FDCR1 is released from FDC-1 cells and other cells as a soluble protein. Thus, they will test whether soluble FDCR1 can regulate human GC-associated B cells, dendritic cells (DCs) and T cells; 3) To test the hypothesis that the C-terminal region of FDCR1 is critical for its receptor functions and FDCR1-regulated mRNA expression; 4) To elucidate novel follicular dendritic cell (FDC)-associated molecules which regulate B cells. They will test if FDCs express novel FDC- specific receptors. Via the powerful PCR Select method, they have already identified three new FDC-associated genes; they will isolate one or more cDNAs encoding FDC-restricted genes, and based on stringent criteria, select one novel gene for further analysis. These studies will contribute to our understanding of the molecular basis of immunological memory, antibody-mediated autoimmune diseases, and GC-associated diseases such as AIDS and lymphomas.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Experimental Immunology Study Section (EI)
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Quill, Helen R
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University of Washington
Veterinary Sciences
Other Domestic Higher Education
United States
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Clark, Edward A; Giltiay, Natalia V (2018) CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity. Front Immunol 9:2235
Chappell, Craig P; Draves, Kevin E; Clark, Edward A (2017) CD22 is required for formation of memory B cell precursors within germinal centers. PLoS One 12:e0174661
Giltiay, Natalia V; Shu, Geraldine L; Shock, Anthony et al. (2017) Targeting CD22 with the monoclonal antibody epratuzumab modulates human B-cell maturation and cytokine production in response to Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) signaling. Arthritis Res Ther 19:91
Chappell, Craig P; Giltiay, Natalia V; Draves, Kevin E et al. (2014) Targeting antigens through blood dendritic cell antigen 2 on plasmacytoid dendritic cells promotes immunologic tolerance. J Immunol 192:5789-5801
Giordano, Daniela; Draves, Kevin E; Li, Chang et al. (2014) Nitric oxide regulates BAFF expression and T cell-independent antibody responses. J Immunol 193:1110-20
Chappell, Craig P; Giltiay, Natalia V; Dresch, Christiane et al. (2014) Controlling immune responses by targeting antigens to dendritic cell subsets and B cells. Int Immunol 26:3-11
Chaplin, Jay W; Chappell, Craig P; Clark, Edward A (2013) Targeting antigens to CD180 rapidly induces antigen-specific IgG, affinity maturation, and immunological memory. J Exp Med 210:2135-46
Hughes, Grant C; Clark, Edward A; Wong, Alan H (2013) The intracellular progesterone receptor regulates CD4+ T cells and T cell-dependent antibody responses. J Leukoc Biol 93:369-75
Giltiay, Natalia V; Chappell, Craig P; Sun, Xizhang et al. (2013) Overexpression of TLR7 promotes cell-intrinsic expansion and autoantibody production by transitional T1 B cells. J Exp Med 210:2773-89
Kasahara, Shinji; Clark, Edward A (2012) Dendritic cell-associated lectin 2 (DCAL2) defines a distinct CD8?- dendritic cell subset. J Leukoc Biol 91:437-48

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