Sjogren's syndrome is an autoimmune disease affecting mainly the salivary and lacrimal glands. As a result of leukocyte infiltration and various immune reactions, the secretory function of the glands is impaired resulting in dry eyes and dry mouth. Systemic manifestation can be present and other exocrine glands can be affected. What triggers the leukocyte infiltration into the salivary and lacrimal glands remains unknown. It is nearly impossible to address this issue in humans because of the long lag time between the """"""""initial triggering event"""""""" and the eventual diagnosis of disease. Mouse models for Sjogren's syndrome have been valuable. However, each model studied so far seems to display unique characteristics reflecting only a particular aspect of the disease. In addition, the time for the development of disease remains relatively long. Thus, models in which the Sjogren's syndrome develops rapidly and models that are based on rational and fundamental concept are needed. Day 3 post-natal thymectomy induces sialoadenitis in a few strains studied, presumably by removing salivary gland antigen-specific regulatory T (Treg) cells. This report and the recent explosive advance of Treg cell study prompted us to hypothesize that Treg cell-deficient mice must display Sjogren's syndrome among the multiple organs affected. Indeed, we observed severe Sjogren's syndrome in interleukin-2 receptor alpha (IL-2Ralpha) knockout (KO) mice, IL-2 KO mice and scurfy mice all of them lack Treg cells. Remarkably, the development of Sjogren's syndrome is rapid (<1-4 months). Moreover, we developed adoptive transfer model in which the disease could be detected as early as 10 days after high dose leukocyte transfer. This application is based on these newly developed animal models to further advance the study of Sjogren's syndrome. We have 3 specific aims: (1) to establish that Treg cell-deficient mice truly express Sjogren's syndrome and these mice can be used as models for Sjogren's syndrome study;(2) to establish an accelerated model of Sjogren's syndrome using adoptive transfer approach and (3) to study the trigger of Sjogren's syndrome to understand the environment, self antigens, and pathogens in this process. This study should identify new and useful models for Sjogren's syndrome research. It should identify new mechanism(s) for the pathogenesis of the disease and provide potential treatment of the disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017570-05
Application #
7849044
Study Section
Special Emphasis Panel (ZDE1-YL (33))
Program Officer
Burgoon, Penny W
Project Start
2006-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$336,217
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
Sharma, Rahul; Sung, Sun-Sang J; Gaskin, Felicia et al. (2012) A novel function of IL-2: chemokine/chemoattractant/retention receptor genes induction in Th subsets for skin and lung inflammation. J Autoimmun 38:322-31
Ju, Shyr-Te; Sharma, Rahul; Gaskin, Felicia et al. (2012) IL-2 controls trafficking receptor gene expression and Th2 response for skin and lung inflammation. Clin Immunol 145:82-8
Sharma, Rahul; Sharma, Poonam R; Kim, Young-Chul et al. (2011) IL-2-controlled expression of multiple T cell trafficking genes and Th2 cytokines in the regulatory T cell-deficient scurfy mice: implication to multiorgan inflammation and control of skin and lung inflammation. J Immunol 186:1268-78
Sharma, Rahul; Fu, Shu Man; Ju, Shyr-Te (2011) IL-2: a two-faced master regulator of autoimmunity. J Autoimmun 36:91-7
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
Sharma, Rahul; Ju, Shyr-Te (2010) Genetic control of the inflammatory T-cell response in regulatory T-cell deficient scurfy mice. Clin Immunol 136:162-9
Sharma, Rahul; Sung, Sun-sang Joe; Abaya, Christian E et al. (2009) IL-2 regulates CD103 expression on CD4+ T cells in Scurfy mice that display both CD103-dependent and independent inflammation. J Immunol 183:1065-73
Sharma, Rahul; Deshmukh, Umesh S; Zheng, Lingjie et al. (2009) X-linked Foxp3 (Scurfy) mutation dominantly inhibits submandibular gland development and inflammation respectively through adaptive and innate immune mechanisms. J Immunol 183:3212-8
Sharma, Rahul; Ju, Angela Chiao-Ying; Kung, John T et al. (2008) Rapid and selective expansion of nonclonotypic T cells in regulatory T cell-deficient, foreign antigen-specific TCR-transgenic scurfy mice: antigen-dependent expansion and TCR analysis. J Immunol 181:6934-41
Zheng, Lingjie; Sharma, Rahul; Kung, John T et al. (2008) Pervasive and stochastic changes in the TCR repertoire of regulatory T-cell-deficient mice. Int Immunol 20:517-23

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