Sjogren's syndrome (SjS) is a chronic autoimmune disease that affects 2-4 million Americans and greatly affects the health and well-being of the patients. SjS is characterized by chronic inflammation and dysfunction of the salivary and lacrimal glands with dry mouth and dry eyes as the primary symptoms. Autoreactive effector T cells and T cell-derived cytokines play a crucial role in the development and onset of SjS. Interleukin-7 (IL-7) plays a crucial pathogenic role in multiple autoimmune diseases through enhancing T helper (Th) 1 and T cytotoxic (Tc) 1 responses. Elevated IL-7 levels were reported in primary SjS patients. Our preliminary studies showed that both exogenous and endogenous IL-7 promotes the development and onset of SjS in a mouse disease model, which is accompanied by enhanced Th1 and Tc1 responses. In addition, we found that IFN-? and IFN-? can induce IL-7 production in a human salivary gland cell line. In the current study, we will characterize the in vivo functions of IL-7 and its targets in the development and the persistence of primary SjS, and define the signaling and molecular pathways that cause excessive IL-7 production in SjS.
In Aim 1 of this study, we will assess the in vivo functions of IL-7 and IL-7-induced Th1/Tc1 cytokines in the development of SjS and in the persistence of SjS after disease onset. We will use in vivo antibody blockade approach to abrogate IL-7, IFN-? or TNF-? activity at specific stages of the disease in C57BL/6.NOD-Aec1Aec2 mice, a well-defined model of primary SjS.
In Aim 2, we will determine the molecular mechanisms by which IL-7 enhances Th1/Tc1 responses. We will use several genetically mutant mice, in vivo antibody blockade and in vitro gene-silencing approaches to determine the role of T-bet, PD-1 and TRAF1 in IL-7-mediated enhancement of Th1/Tc1 responses. Moreover, we will collaborate with Dr. Seunghee Cha at the University of Florida to validate these results in human T cells from SjS patients and healthy controls, using in vitro T cell stimulation cultures and gene-silencing approaches.
In Aim 3, we will characterize the signaling pathways that cause excessive IL-7 production in salivary gland cells in SjS. We will use several genetically mutant mice, a human epithelial cell line and a combination of in vivo and in vitro approaches to characterize the in vivo role of IFN-? and IFN-? in enhancing IL-7 production from salivary gland cells in the SjS setting. Completion of this project will provide crucial information and foundation for the development of novel diagnostic and therapeutic strategies for SjS by targeting IL-7 and Th1/Tc1 cytokines.

Public Health Relevance

Sjogren's syndrome is a chronic, systemic autoimmune disease that affects 2-4 million Americans and greatly compromises the health and well-being of the patients. Completion of this project will facilitate the development of novel diagnostic and treatment strategies for Sjogren's syndrome by targeting interleukin-7, and will also advance the translational and clinical study of many other immune-mediated diseases. These accomplisments will benefit millions of patients afflicted with Sjogren's syndrome or other immune-mediated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
1R01DE023838-01
Application #
8614323
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Burgoon, Penny W
Project Start
2014-04-10
Project End
2019-01-31
Budget Start
2014-04-10
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$480,477
Indirect Cost
$230,477
Name
Forsyth Institute
Department
Type
DUNS #
062190616
City
Cambridge
State
MA
Country
United States
Zip Code
02142