The goal of the Project 2 of the SLE SCOR is to investigate the mechanism whereby the lupus autoimmune response is initiated and propagated, leading to renal and salivary gland immunopathology. The study will use, as a model lupus autoantigen (Ag), mouse Ro60. The central hypothesis is: systemic autoimmune disease like SLE can result from the single pivotal event of a strong and persistent T cell response to a foreign or unrelated self peptide that mimics the target self T cell peptide. It is supported by the following observations. Through sharing of a critical residue motif with self peptide, a foreign T cell peptide induces autoimmune response and disease. Once triggered, the helper T cell response is rapidly followed by an autoantibody (autoAb) response that is diversified to distant epitopes. The diversified autoAb response, which depends on the presence of endogenous Ag, can be adoptively transferred by Ro60 specific T cell line, and cause SLE-like renal immunopathology. Moreover, the neonatal period is most susceptible to induction of autoAb response and epitope spreading. The project has three Specific Aims:
The first Aim will study the nature of T cell response that mediates autoAb production, resulting in renal and salivary gland pathology. Mouse Ro60 specific T cell clones will be made, their cognate Ro60 peptide, their phenotype and ability to adoptively transfer autoAb and disease defined. The genes encoding the Ro60 T cell receptor (TCR) will be cloned and used to generate TCR transgenic mice. The transgenic mice will be studied for spontaneous autoAb and pathology. To further enhance and dissect the autoimmune response, the mice will be manipulated, as follows: 1) non- transgenic T cell elimination by rendering the mice RAG or TCR-V alpha deficient, 2) to stimulate with adjuvant, 3) to be made B cell deficient, 4) infusion of recombinant mouse Ro60 or apoptotic cell nuclei, and 5) study the responses of normal mice given a finite number of transgenic T cells.
The second Aim will study the response of neonatal mice to the Ro60 T cell epitope. We will fully characterize the neonatal Th2-dominant T cell autoimmune response and memory to self Ag; and determine whether this will lead to Ro60 autoAb response through epitope spreading, and renal immunopathology.
The third Aim will study the mechanisms of molecular mimicry in SLE. To address whether self B cell activation is the initiating event, we will immunize mice with chimeric peptides containing native Ro60 B cell epitope and foreign T cell peptide, and study T cell response to Ro60, autoAb diversification and disease. Finally, mimicry at the Ro60 T cell epitope through sharing of critical residue motif will be investigated.

Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
United States
Zip Code
Sung, Sun-Sang J; Ge, Yan; Dai, Chao et al. (2017) Dependence of Glomerulonephritis Induction on Novel Intraglomerular Alternatively Activated Bone Marrow-Derived Macrophages and Mac-1 and PD-L1 in Lupus-Prone NZM2328 Mice. J Immunol 198:2589-2601
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
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
Lewis, Janet E; Fu, Shu Man; Gaskin, Felicia (2013) Autoimmunity, end organ damage, and the origin of autoantibodies and autoreactive T cells in systemic lupus erythematosus. Discov Med 15:85-92
Ge, Yan; Brown, Michael G; Wang, Hongyang et al. (2012) Genetic approach to study lupus glomerulonephritis. Methods Mol Biol 900:271-90
Fu, Shu Man; Deshmukh, Umesh S; Gaskin, Felicia (2011) Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR. J Autoimmun 37:104-12
Deshmukh, Umesh S; Sim, Davis L; Dai, Chao et al. (2011) HLA-DR3 restricted T cell epitope mimicry in induction of autoimmune response to lupus-associated antigen SmD. J Autoimmun 37:254-62
Jiang, Chao; Deshmukh, Umesh S; Gaskin, Felicia et al. (2010) Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens. J Immunol 184:1085-91
Sharma, Rahul; Sung, Sun-sang Joe; Fu, Shu Man et al. (2009) Regulation of multi-organ inflammation in the regulatory T cell-deficient scurfy mice. J Biomed Sci 16:20
Bagavant, Harini; Fu, Shu Man (2009) Pathogenesis of kidney disease in systemic lupus erythematosus. Curr Opin Rheumatol 21:489-94

Showing the most recent 10 out of 42 publications