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
Seror, Raphaèle; Theander, Elke; Brun, Johan G et al. (2015) Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 74:859-66
Altorok, Nezam; Coit, Patrick; Hughes, Travis et al. (2014) Genome-wide DNA methylation patterns in naive CD4+ T cells from patients with primary Sjögren's syndrome. Arthritis Rheumatol 66:731-9
Rasmussen, Astrid; Ice, John A; Li, He et al. (2014) Comparison of the American-European Consensus Group Sjogren's syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterised sicca cohort. Ann Rheum Dis 73:31-8
Maier-Moore, Jacen S; Horton, Christopher G; Mathews, Shirley A et al. (2014) Interleukin-6 deficiency corrects nephritis, lymphocyte abnormalities, and secondary Sjögren's syndrome features in lupus-prone Sle1.Yaa mice. Arthritis Rheumatol 66:2521-31
Maier-Moore, Jacen S; Koelsch, Kristi A; Smith, Kenneth et al. (2014) Antibody-secreting cell specificity in labial salivary glands reflects the clinical presentation and serology in patients with Sjögren's syndrome. Arthritis Rheumatol 66:3445-56
Igoe, Ann; Scofield, R Hal (2013) Autoimmunity and infection in Sjogren's syndrome. Curr Opin Rheumatol 25:480-7
Lessard, Christopher J; Li, He; Adrianto, Indra et al. (2013) Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat Genet 45:1284-92