Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease that affects predominantly females in their productive ages. It causes significant morbidity and mortality. Despite considerable progress in our understanding of its pathogenesis, effective therapies without significant side effects for induction and prevention of relapse are wanting. Our research in lupus genetics and the mechanism of diversification of lupus related autoantibodies and the insight gained in taking care of these patients led us to postulate the hypothesis that takes into consideration the three main features of SLE: 1) the HLA-D complex is a dominant genetic loci for disease susceptibility;2) there is a considerable latent period between the detection of the first autoantibody (auto-Ab) and clinical manifestation with evidence of auto-Ab diversification;and 3) both the initial clinical presentation and relapses are protean in that one or more organs can be involved in an apparently stochastic fashion. Our hypothesis states that lupus susceptibility genes exert their effect on either autoimmunity or resistance to end organ damage. Autoantibodies are generated by the activation of cross-reactive T cells to environmental antigens and lupus related autoantigens in a HLA-DR restricted fashion. Over a period of time (years in man), the culmination of these autoreactive T cells occurs, resulting in diverse auto-Ab responses and initial clinical presentation in susceptible hosts. Remission results from the reduction of these autoreactive T cells and the reduction of diversification of auto-Ab relativities. Relapses occur with repeated stimulation of molecular mimics in hosts with heightened basal activation levels in their immune system. The clinical presentation in relapses depends on the nature of the mimics. In this competitive renewal application, experiments are proposed to seek evidence to support this hypothesis.
Three aim are proposed: 1) To elucidate the mechanisms of autoantibody diversification;2) To generate TCR transgenic mice with single and dual (multiple) specificities to provide a large number of autoreactive T cells to establish adoptive transfer models to study the activation of single vs dual reactive T cells in vitro and in vivo;and 3) To demonstrate that NZM2328.DR3 and its congenic lines such as NZM2328.c1R27DR3 mice that have no endogenous class II antigen are suitable hosts for antigen induced auto-Ab and are good models for induction of remission and relapses. The expected results of the proposed experiments will support our hypothesis. Our hypothesis is novel and challenges the current paradigms in the pathogenesis of SLE. It provides a logical explanation for the three main features of SLE. It gives a frame work for the identification of seeking biomarkers for responsiveness to inductive treatments for remission and for maintenance therapies. The hypothesis identifies logical targets for therapeutic interventions.

Public Health Relevance

This is a renewal application to study causes of systemic lupus erythematosus (SLE). SLE causes significant economic loss and suffering. We have evidence to support the thesis that lupus autoantibody production is the result of immune responses to bacterial or viral molecules that can stimulate some T cells, which are also reactive with self antigen. In this application we plan to show that these T cells exist in our bodies and that they can respond to multiple antigens. These cells accumulate in our body over a period of time, resulting in the production of autoantibodies to multiple autoantigens and autoreactive T cells. These antibodies and T cells cause damage to various organs, resulting in various clinical presentations during the initial diagnosis of the disease and during flares. Clinical diseases occur in genetically susceptible individuals whose white cells are more reactive and/or their end organs are more susceptible to damage. The results of the proposed studies may allow us to identify objective markers that indicate sufficient initial treatments for the induction of remission and that our therapy is effective for maintenance of remission. The new knowledge obtained from the proposed experiments challenges the current dogma and will have an impact on our ability to treat patients with active disease and to maintain the patients'quality of life.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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

Showing the most recent 10 out of 31 publications