Systemic lupus erythematosus (SLE) is a complex, autoimmune disorder predominantly affecting young females. Despite being multigenic, the HLA complex in general and HLA-DR in particular remains the most dominant genetic risk factor for disease susceptibility. A striking feature is the strong association of autoantibody specificities with some HLA haplotypes. This proposal addresses the mechanisms for this close association. In this proposal we will test the hypotheses that in lupus patients, molecular mimicry with microbial peptides is responsible for the selective enrichment of T cells reactive with lupus- associated autoantigens. Depending on microbial exposure, the HLA dictates the nature of cross- reactive peptides it binds and thereby the autoantigen selection. This process leads to activation of self- reactive T cells, autoantibody production, epitope spreading and end organ damage. Using Ro60 as the candidate autoantigen and HLA-DR and -DQ transgenic mice, following specific aims are proposed: to seek evidence for our hypothesis 1) To identify the molecular mimics of T cell epitopes on Ro60. 2) To demonstrate that multiple exposures to peptide mimics of Ro60 T cell epitopes influences the Ro60 reactive T cell repertoire. 3) To determine the pathogenic potential of anti-Ro60 initiated autoimmune responses in lupus-prone NZM2328 mice transgenic for HLA-DR3 and -DQ2. The findings from this proposal will clearly demonstrate that T cell responses to lupus-associated antigens can initiate autoimmune responses in SLE. This will shift the current paradigm that SLE is predominantly a B cell mediated disease to a more rational model in which both T and B cells have their unique roles in disease manifestation. This will provide a theoretical framework from which rational therapeutic approach can be devised.

Public Health Relevance

The current proposal will identify proteins from infectious agents that might initiate an autoimmune response in systemic lupus erythematosus. This will identify infectious microorganisms that can be predisposing factors for the development of an autoimmune disorder such as lupus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079621-04
Application #
8291356
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Johnson, David R
Project Start
2009-07-16
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$424,512
Indirect Cost
$144,306
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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
Bagavant, H; Nandula, S R; Kaplonek, P et al. (2014) Alum, an aluminum-based adjuvant, induces Sjögren's syndrome-like disorder in mice. Clin Exp Rheumatol 32:251-5
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
Nackiewicz, Dominika; Dey, Paromita; Szczerba, Barbara et al. (2014) Inhibitor of differentiation 3, a transcription factor, regulates hyperlipidemia-associated kidney disease. Nephron Exp Nephrol 126:141-7
Szczerba, B M; Rybakowska, P D; Dey, P et al. (2013) Type I interferon receptor deficiency prevents murine Sjogren's syndrome. J Dent Res 92:444-9
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
Nandula, Seshagiri-Rao; Dey, Paromita; Corbin, Kathryn L et al. (2013) Salivary gland hypofunction induced by activation of innate immunity is dependent on type I interferon signaling. J Oral Pathol Med 42:66-72
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
Deshmukh, Umesh S; Bagavant, Harini (2013) When killers become helpers. Sci Transl Med 5:195fs29
Sharma, Rahul; Sung, Sun-Sang J; Ju, Chiao-Ying A et al. (2011) Regulatory T-Cell (Treg) hybridoma as a novel tool to study Foxp3 regulation and Treg fate. J Autoimmun 37:113-21

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