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 #
1P50AR060804-01
Application #
8102494
Study Section
Special Emphasis Panel (ZAR1-MLB (M1))
Project Start
2011-07-21
Project End
2016-06-30
Budget Start
2011-07-21
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$417,776
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Leehan, Kerry M; Pezant, Nathan P; Rasmussen, Astrid et al. (2017) Minor salivary gland fibrosis in Sjögren's syndrome is elevated, associated with focus score and not solely a consequence of aging. Clin Exp Rheumatol :
Sandhya, Pulukool; Kurien, Biji Theyilamannil; Danda, Debashish et al. (2017) Update on Pathogenesis of Sjogren's Syndrome. Curr Rheumatol Rev 13:5-22
Zhao, Jian; Ma, Jianyang; Deng, Yun et al. (2017) A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet 49:433-437
Shiboski, Caroline H; Shiboski, Stephen C; Seror, Raphaèle et al. (2017) 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjögren's Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol 69:35-45
Li, He; Reksten, Tove Ragna; Ice, John A et al. (2017) Identification of a Sjögren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet 13:e1006820
Stone, Donald U; Fife, Dustin; Brown, Michael et al. (2017) Effect of Tobacco Smoking on The Clinical, Histopathological, and Serological Manifestations of Sjögren's Syndrome. PLoS One 12:e0170249
Carapito, Raphael; Gottenberg, Jacques-Eric; Kotova, Irina et al. (2017) A new MHC-linked susceptibility locus for primary Sjögren's syndrome: MICA. Hum Mol Genet 26:2565-2576
Leehan, Kerry M; Pezant, Nathan P; Rasmussen, Astrid et al. (2017) Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren's syndrome. Autoimmunity 50:451-457
Talsania, Mitali; Scofield, Robert Hal (2017) Menopause and Rheumatic Disease. Rheum Dis Clin North Am 43:287-302
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

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