EXCEED THE SPACE PROVIDED. B-cell tolerance is affected by central and peripheral censoring mechanisms at several checkpoints. Dysregulation at these checkpoints can potentially lead to humeral autoimmunity. To what extent these checkpoints are infringed in spontaneous, systemic autoimmune disease remains unknown. A major challenge of contemporary autoimmunity research is to fathom the precise mechanisms that tip the balance from tolerance towards autoimmunity, in spontaneous disease. The availability of B6 mice bearing different lupus susceptibility loci, as congenic intervals, now allows us to ask how these loci might compromise B cell tolerance. In particular, in this proposal, we will utilize B6.congenics bearing five different NZM2410-derived lupus susceptibility loci. The goals of this proposal are: (1) To ascertain the impact of lupus susceptibility loci (Slela, Slelb, Sle2, Sle3 and Sle5) to DNA, using anti-DNA immunoglobulin transgenic mice. (2) To ascertain the impact of lupus susceptibility loci (Slela, Slelb, Sle2, Sle3 and Sle5) to non-nuclear antigens, using the anti-HEL immunoglobulin transgenic model. (3) To elucidate the molecular pathways that may be infringed by the lupus susceptibility tolerance is actively breached, using na=ve B-cells purified from immunoglobulin transgenic on B-cell tolerance on B-cell tolerance loci, as self- models. Collectively, the above studies will indicate how loci/genes that predispose to systemic autoimmunity might tip the balance away from self-tolerance. Understanding how these loci/genes function will not only broaden our perspective of this disease, but will also point to potential targets for therapeutic intervention. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR044894-08
Application #
6832789
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Gretz, Elizabeth
Project Start
1998-01-15
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
8
Fiscal Year
2005
Total Cost
$378,300
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Wu, Tianfu; Ye, Yujin; Min, So-Youn et al. (2014) Prevention of murine lupus nephritis by targeting multiple signaling axes and oxidative stress using a synthetic triterpenoid. Arthritis Rheumatol 66:3129-39
Liang, Zhiyan; Chang, Sooghee; Youn, Min So et al. (2009) Molecular hallmarks of anti-chromatin antibodies associated with the lupus susceptibility locus, Sle1. Mol Immunol 46:2671-81
Xie, Chun; Patel, Rahul; Wu, Tianfu et al. (2007) PI3K/AKT/mTOR hypersignaling in autoimmune lymphoproliferative disease engendered by the epistatic interplay of Sle1b and FASlpr. Int Immunol 19:509-22
Wu, Tianfu; Qin, Xiangmei; Kurepa, Zoran et al. (2007) Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J Clin Invest 117:2186-96
Kumar, Kirthi Raman; Li, Liunan; Yan, Mei et al. (2006) Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science 312:1665-9
Wakui, Masatoshi; Morel, Laurence; Butfiloski, Edward J et al. (2005) Genetic dissection of systemic lupus erythematosus pathogenesis: partial functional complementation between Sle1 and Sle3/5 demonstrates requirement for intracellular coexpression for full phenotypic expression of lupus. J Immunol 175:1337-45
Sobel, Eric S; Morel, Laurence; Baert, Raquel et al. (2002) Genetic dissection of systemic lupus erythematosus pathogenesis: evidence for functional expression of Sle3/5 by non-T cells. J Immunol 169:4025-32
Mohan, C; Yu, Y; Morel, L et al. (1999) Genetic dissection of Sle pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. J Immunol 162:6492-502