Primary Sjogren's Syndrome (SS) is a common, debilitating disease characterized by lymphocytic infiltrates in exocrine tissue. Understanding of SS pathogenesis and development of effective biologic therapies for SS have been hampered by a lack of strategies for deciphering the specificities and differentiation states of antigen-specific T cells in the targeted tissue. We are in a unique position to address this important challenge due to i) establishment of the successful OMRF Sjogren's Research Clinic, ii) available expertise in proteomics and single cell RT-PCR of lymphocyte receptors, iii) recent discovery of HLA DR3-restricted T cell epitopes of the canonical SS autoantigens and iv) recruitment of strong collaborators who will work with us to transfer a novel T cell receptor (TCR) RNA transfection technology from the field of cancer to autoimmunity. Novel biologic therapies directed against new pathogenic T helper (Th) cell types including Th17 and T follicular helper (TFH) cells are being developed and could be applied to SS if predominant Th differentiation states in SS were known.
In Aim 1 we will use a systematic single cell RT-PCR approach to characterize the TCR repertoire of CD4+ and CD8+ T cells isolated from paired labial salivary gland (SG) biopsy and peripheral blood (PB) samples of SS patients. Evaluation of these data for evidence of T cell clonal expansion and common TCR segment usage or CDRS motifs will disclose evidence for or against involvement of CD8+ T cells in SS and will identify CD4+ or CD8+ TCRs that are expanded in situ within the inflammatory lesion.
In Aim 2, we will synthesize and validate DRS tetramer reagents that will detect Th cells specific for the primary known SS autoantigens Ro/SS-A and La/SS-B. These reagents will be exploited to quantify the frequency of these cells and to determine their predominant memory and Th differentiation states in SG and PB. The relationship(s) of these features to serum Type I interferon activity and measures of disease are expected to lead to insights into SS pathogenesis.
In Aim S we will use a proteomic approach to identify SG antigens recognized by T cells that are clonally expanded in SG of SS patients, a strategy made feasible by the robust TCR RNA transfection technique of our collaborators.

Public Health Relevance

This proposal uses several innovative approaches to reveal key features of immune dysregulation in Sjogren's syndrome, a common and debilitating disease. Moreover, knowledge obtained from completion of these studies will not only facilitate the selection, application, and monitoring of appropriate novel biologic therapies in SS but will further provide new tools for understanding effective immunity in cancer and Infectious diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Specialized Center (P50)
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Special Emphasis Panel (ZAR1)
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Oklahoma Medical Research Foundation
Oklahoma City
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Vivino, Frederick B; Carsons, Steven E; Foulks, Gary et al. (2016) New Treatment Guidelines for Sjögren's Disease. Rheum Dis Clin North Am 42:531-51
Fayyaz, Anum; Kurien, Biji T; Scofield, R Hal (2016) Autoantibodies in Sjögren's Syndrome. Rheum Dis Clin North Am 42:419-34
Szczerba, Barbara M; Kaplonek, Paulina; Wolska, Nina et al. (2016) Interaction between innate immunity and Ro52-induced antibody causes Sjögren's syndrome-like disorder in mice. Ann Rheum Dis 75:617-22
Pan, Z-J; Horton, C G; Lawrence, C et al. (2016) Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3(+) regulatory T cells specific for the ubiquitous RNA-binding nuclear antigen La/Sjögren's syndrome (SS)-B. Clin Exp Immunol 186:18-29
Sandhya, Pulukool; Kurien, Biji Theyilamannil; Danda, Debashish et al. (2016) Update on Pathogenesis of Sjögren's syndrome. Curr Rheumatol Rev :
Joachims, Michelle L; Leehan, Kerry M; Lawrence, Christina et al. (2016) Single-cell analysis of glandular T cell receptors in Sjögren's syndrome. JCI Insight 1:
Harris, Valerie M; Sharma, Rohan; Cavett, Joshua et al. (2016) Klinefelter's syndrome (47,XXY) is in excess among men with Sjögren's syndrome. Clin Immunol 168:25-9
Rasmussen, Astrid; Radfar, Lida; Lewis, David et al. (2016) Previous diagnosis of Sjögren's Syndrome as rheumatoid arthritis or systemic lupus erythematosus. Rheumatology (Oxford) 55:1195-201
Wolska, Nina; Rybakowska, Paulina; Rasmussen, Astrid et al. (2016) Brief Report: Patients With Primary Sjögren's Syndrome Who Are Positive for Autoantibodies to Tripartite Motif-Containing Protein 38 Show Greater Disease Severity. Arthritis Rheumatol 68:724-9
Nocturne, Gaetane; Tarn, Jessica; Boudaoud, Saida et al. (2016) Germline variation of TNFAIP3 in primary Sjögren's syndrome-associated lymphoma. Ann Rheum Dis 75:780-3

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