The underlying premise of this proposal is that increased in vivo production of B cell activating factor belonging to the TNF family (BAFF), a vital B cell survival and costimulatory factor, is an important and central contributor to disease development and/or maintenance in many, but not necessarily all, SLE patients. The entry of BAFF antagonists into human clinical trials notwithstanding, a greater insight into several critical issues is needed before treatment with BAFF antagonists can realize their full clinical potential. First, in vivo conditions under which BAFF overexpression leads to disease versus those under which BAFF overexpression does not lead to disease have largely been unexplored. Development of an in vivo model in which BAFF-driven disease rapidly develops would facilitate experimental dissection of the requisite pathways. Conversely, development of an in vivo model in which constitutive overexpression of BAFF is incapable of driving autoimmunity would facilitate dissection of pathways that render resistance to BAFF. Second, the relative importance of the individual BAFF receptors to BAFF-driven autoimmune disease is not known and needs to be identified. Third, it is not known whether the disease-promoting effects of BAFF are consequent to production of pathogenic autoantibodies or are consequent to effects on B cells that are largely independent of autoantibody production. To begin to address these issues, the following questions are posed: 1a) Does persistent BAFF overproduction synergize with an underlying incomplete genetic predisposition to SLE and result in rapid development of disease? 1 b) Does a SLE suppressor genetic region protect against the disease-promoting effects of persistent BAFF overexpression? 2a) Will elimination of BAFF ameliorate development of autoimmune disease in a SLE-prone host? 2b) Will elimination of BAFFR and/or BCMA ameliorate development of disease in a host that naturally is SLE-prone or in a host with BAFF-driven autoimmune disease? 3) Does BAFF promote autoimmune disease in an autoantibody-independent manner? The results from these in vivo studies in mice should yield important information regarding BAFF-driven disease that will help set a solid foundation for subsequent focused in vivo clinical trials in human SLE patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR050193-05
Application #
7770840
Study Section
Special Emphasis Panel (ZRG1-HAI-K (08))
Program Officer
Mancini, Marie
Project Start
2006-05-16
Project End
2012-08-31
Budget Start
2010-03-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2010
Total Cost
$337,824
Indirect Cost
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Sindhava, Vishal J; Oropallo, Michael A; Moody, Krishna et al. (2017) A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens. J Clin Invest 127:1651-1663
Sindhava, Vishal J; Scholz, Jean L; Stohl, William et al. (2014) APRIL mediates peritoneal B-1 cell homeostasis. Immunol Lett 160:120-7
Goenka, Radhika; Matthews, Andrew H; Zhang, Bochao et al. (2014) Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation. J Exp Med 211:45-56
Shah, Hemangi B; Joshi, Sunil K; Rampuria, Pragya et al. (2013) BAFF- and APRIL-dependent maintenance of antibody titers after immunization with T-dependent antigen and CD1d-binding ligand. J Immunol 191:1154-63
Jacob, Chaim O; Yu, Ning; Guo, Shunhua et al. (2013) Development of systemic lupus erythematosus in NZM 2328 mice in the absence of any single BAFF receptor. Arthritis Rheum 65:1043-54
Stohl, William; Hilbert, David M (2012) The discovery and development of belimumab: the anti-BLyS-lupus connection. Nat Biotechnol 30:69-77
Jacob, Chaim O; Guo, Shunhua; Jacob, Noam et al. (2012) Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. Arthritis Rheum 64:1610-9
Jacob, Noam; Guo, Shunhua; Mathian, Alexis et al. (2011) B Cell and BAFF dependence of IFN-?-exaggerated disease in systemic lupus erythematosus-prone NZM 2328 mice. J Immunol 186:4984-93
Zhou, Xiaohui; Xia, Zanxian; Lan, Qin et al. (2011) BAFF promotes Th17 cells and aggravates experimental autoimmune encephalomyelitis. PLoS One 6:e23629
Jacob, Noam; Stohl, William (2010) Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: past, present, and future. Autoimmunity 43:84-97

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