Sjogren's syndrome is a systemic autoimmune disease that most commonly targets the exocrine glands and is characterized by persistent dry eyes and mouth as well as extra-glandular involvement including blood vessel, skin, kidney, joints, and lung disease along with an increased risk of lymphoma. Salivary gland lymphocytic infiltrates are a pathological finding in the disease. The serum of these patients commonly contains autoantibodies to Ro (SS-A) and La (SS-B). Other specificities are present, including those towards muscarinic receptors. There are strong data supporting significant autoreactive B cell expansion, hyperreactivity and antibody formation in exocrine glands of Sjogren's patient, including the presence of anti-Ro and -La specific B cells. The evidence is strong that B cells infiltrating the salivary glands of Sjogren's patients make autoantibodies that are in part responsible for the exocrine glandular dysfunction. This proposal will test the hypothesis that this is the case, and will address the pathogenic mechanisms underlying this dysfunction. We will utilize an innovative, humanized model of Sjogren's in which human salivary tissue is transplanted into NOD SCID mice. So transplanted mice are already available (see Preliminary Data). In addition, we will use an innovative method of producing recombinant monoclonal antibodies to study the autoantibody repertoire produced in the salivary gland of humans with Sjogren's. Already we have harvested B cells from minor salivary glands and begun the process of producing recombinant monoclonals antibodies (see Preliminary Data). First, we will produce recombinant monoclonal antibodies from B cells infiltrating the salivary glands of humans with Sjogren's syndrome. Then, these monoclonal antibodies will be tested for pathogenicity, that is, the ability to reduce salivary flow in either normal mice, or the xenotransplanted Sjogren's mouse model. We will study the binding specificity of pathogenic autoantibodies. Furthermore, the pathogenic mechanisms by which these antibodies cause the characteristic salivary gland dysfunction will be elucidated.

Public Health Relevance

Sjogren's syndrome is a common, debilitating human autoimmune illness. The causes of the disease are not understood. Treatment is for the symptoms not the underlying mechanisms of how individuals get ill. We will study the manner in which abnormailities of antibody secreting cells, B lymphocytes, are repsonsible for producing this illness. Such knowledge should lead to treatments directs at these cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Specialized Center (P50)
Project #
5P50AR060804-03
Application #
8490322
Study Section
Special Emphasis Panel (ZAR1-MLB)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$360,496
Indirect Cost
$94,205
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
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

Showing the most recent 10 out of 36 publications