Significant progress has been made to elucidate the mechanism of lupus autoantibody diversification and to identify important HLA-D restriction elements in response to SLE-related autoantigens. Crossreactive autoantibodies and the expansion of antigen-specific T cells reactive to one or more SLE-related autoantigens are important in the diversification of autoantibody response. With current available transgenic mice expressing D region molecules, DR2 and DR3 are the dominant determinants controlling the magnitude of the precipitating antibody response to recombinant Ro60, and for intermolecular epitope spreading to Ro52. With SmD as the immunogen, DR3 and DQ6 (DQ6B1*0602) were shown to be dominant in the generation of specific anti-SmD antibodies. In DR3 transgenic mice, intermolecular B epitope spreading to A-RNP, C-RNP, and SmB was found. In the case of the DQ6 transgenics, specific antibodies to A-RNP and SmB were detected. In addition, a new model of lupus prone mice, NZM2328 has been characterized and two unique congenic lines have been generated. The NZM2328 and its congenic lines will be useful in the proposed experiments. Based on these findings, this application is to explore the role of HLA-D region and T epitopes in SLE related autoantigens in the pathogenesis of SLE.
Four specific aims are proposed.
Specific Aim 1 : To determine the role of HLA-D molecules in the pathogenesis of SLE.
Specific Aim 2 : To complete the mapping of T and B epitopes of the selected SLE related antigen SmD and to determine the mechanism of autoantibody diversification.
Specific Aim 3 : To determine the structural requirement for peptides from SLE related autoantigens.
Specific Aim 4 : To determine whether T cells reactive to DR restricted peptides mapped in specific aim 2 are present in patients with lupus and in normal controls. This proposal will provide significant information regarding the role of T cell receptor degeneracy, T cell epitopes and molecular mimicry in the induction of autoimmunity in SLE. The proposed experiments will provide new information regarding autoantibody diversification and may also provide data or clues regarding the nature of the initiating antigens. In addition, experiments are proposed to test directly whether HLA-D genes can directly support the development of SLE. The understanding of the role of HLA- D region in the pathogenesis of SLE and the initiation events is crucial in our approach for the prevention and therapy of this disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049449-03
Application #
7271175
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
2005-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$327,922
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Fu, Shu Man; Wang, Hongyang; Dai, Chao et al. (2017) Pathogenesis of proliferative lupus nephritis from a historical and personal perspective. Clin Immunol 185:51-58
Zhao, Jijun; Wang, Hongyue; Huang, Yuefang et al. (2015) Lupus nephritis: glycogen synthase kinase 3? promotion of renal damage through activation of the NLRP3 inflammasome in lupus-prone mice. Arthritis Rheumatol 67:1036-44
Chowdhary, Vaidehi R; Dai, Chao; Tilahun, Ashenafi Y et al. (2015) A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus. J Immunol 195:4660-7
Zhang, Hui; Huang, Yuefang; Wang, Shuang et al. (2015) Myeloid-derived suppressor cells contribute to bone erosion in collagen-induced arthritis by differentiating to osteoclasts. J Autoimmun 65:82-9
Zhang, Hui; Wang, Shuang; Huang, Yuefang et al. (2015) Myeloid-derived suppressor cells are proinflammatory and regulate collagen-induced arthritis through manipulating Th17 cell differentiation. Clin Immunol 157:175-86
Dai, Chao; Deng, Yun; Quinlan, Aaron et al. (2014) Genetics of systemic lupus erythematosus: immune responses and end organ resistance to damage. Curr Opin Immunol 31:87-96
Dai, Chao; Wang, Hongyang; Sung, Sun-Sang J et al. (2014) Interferon alpha on NZM2328.Lc1R27: enhancing autoimmunity and immune complex-mediated glomerulonephritis without end stage renal failure. Clin Immunol 154:66-71
Szymula, Agnieszka; Rosenthal, Jacob; Szczerba, Barbara M et al. (2014) T cell epitope mimicry between Sjögren's syndrome Antigen A (SSA)/Ro60 and oral, gut, skin and vaginal bacteria. Clin Immunol 152:1-9
Zhao, Jijun; Wang, Hongyue; Dai, Chao et al. (2013) P2X7 blockade attenuates murine lupus nephritis by inhibiting activation of the NLRP3/ASC/caspase 1 pathway. Arthritis Rheum 65:3176-85
Ge, Yan; Jiang, Chao; Sung, Sun-Sang J et al. (2013) Cgnz1 allele confers kidney resistance to damage preventing progression of immune complex-mediated acute lupus glomerulonephritis. J Exp Med 210:2387-401

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