The TNF-family cytokine BAFF is a produced by a number of cell types including dendritic cells (DCs), lymphocytes and stromal cells. BAFF is essential for mature B cells to develop and to respond to antigens (Ags). Dysregulation of BAFF contributes to autoimmune diseases like systemic lupus erythematosus (SLE) and to B cell malignancies. Little is known about when, where and how BAFF is produced in vivo and about which BAFF- producing cells contribute to B cell maturation, B cell responses and B cell-associated diseases. We will address this by using two novel transgenic (Tg) mouse lines we have developed: BAFF reporter (BAFF.TRT) and BAFF floxed (BAFFfl/fl) mice. We will define how tissue and cell specific expression of BAFF is regulated and determine which BAFF- producing cells contribute to immune responses and B cell-associated autoimmune disease.
In Aim 1 will use BAFF.TRT reporter mice to determine which cells upregulate BAFF after exposure to Ags or Salmonella typhimurium that induce extrafollicular (EF) antibody (Ab) responses. Using BAFFfl/fl mice crossed to Cre recombinase lines that are missing BAFF in dendritic cells (DCs), macrophages and/or neutrophils, we will define which cells must produce BAFF for EF responses to develop.
In Aim 2 will use BAFF.TRT reporter mice to determine which cells upregulate BAFF after exposure to Ags or Salmonella typhimurium that induce germinal center (GC) formation, memory B cell and long lived plasma cells. We will investigate the role of myeloid-, T cell- and follicular dendritic cell-derived BAFF in these humoral immune responses.
In Aim 3 we will define how BAFF is regulated during the development of autoimmune disease and the sources of BAFF required for the development of autoAbs and disease. We will cross B6.BAFF.TRT reporter and certain B6.BAFFfl/fl conditional knockout mice to B6.Sle1 and B6.TLR7 transgenic mice that develop lupus-like autoimmunity to define how dysregulated TLR7 affects BAFF expression and BAFF-dependent autoimmune disease. These studies will impact our understanding of and how best to vaccinate to generate long-lived humoral immunity and how to treat BAFF-driven disease processes.

Public Health Relevance

The cytokine B cell activating factor (BAFF) is required for B cells to mature and, when dysregulated can help promote autoimmune diseases like systemic lupus erythematosus (SLE). We will define the sources of BAFF required for important antibody responses and for promoting SLE-like autoimmune disease. These studies may lead to new insights on how best to vaccinate against infections and prevent and treat autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI044257-16A1
Application #
9054002
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ferguson, Stacy E
Project Start
1998-12-01
Project End
2020-08-31
Budget Start
2015-12-01
Budget End
2016-11-30
Support Year
16
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Clark, Edward A; Giltiay, Natalia V (2018) CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity. Front Immunol 9:2235
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; Draves, Kevin E; Clark, Edward A (2017) CD22 is required for formation of memory B cell precursors within germinal centers. PLoS One 12:e0174661
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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