M3 Receptor--Diagnostic Marker for Sjogren's Syndrome

描述（由申请人提供）：干燥综合征是一种人类唾液和泪腺自身免疫性疾病，可导致衰弱性口干症（口干）和干眼症（眼干）。该综合征可表现为原发性自身免疫性疾病或继发性自身免疫性疾病，最常伴有其他结缔组织疾病或糖尿病。虽然被归类为孤儿病，干燥综合征的诊断严重不足；因此，据估计，实际上有多达200万至400万人（其中90%是女性）患有这种疾病。目前，干燥综合征的诊断需要在唇腺活检中检测淋巴细胞浸润；类风湿因子的存在，与细胞成分反应的血清抗体（例如，SS-A/Ro, SS-B/La， α -fodrin和/或核因子），高γ -球蛋白血症和外分泌腺流速下降。这些标记物本身都不是疾病特异性的。最近，我们和其他研究人员发现，所有干燥综合征患者的血清中都含有外分泌组织中表达的3型毒蕈碱乙酰胆碱受体（M3R）的抗体。因此，这种自身抗原似乎是能够定义自身免疫性外皮病的单一标记物。在I期授权下开展的工作表明，建立一种基于elisa的检测方法的可行性，该方法利用全长重组人M3R来检测干燥综合征患者的抗M3R自身抗体。因此，该II期资助的具体目标是：1)完成基于elisa的检测方法的开发；2)获得基于elisa的检测方法的分析和临床性能数据；3)确定抗m3r自身抗体检测与干燥综合征患者疾病预测之间的精确关联。一种简单的、非手术的、干燥综合征特异性诊断测试的最终发展将是对患者、治疗医生和临床实验室的一个可喜的补充。

DESCRIPTION (provided by applicant): Sjogren's syndrome is a human autoimmune disease of the salivary and lacrimal glands that results in a debilitating xerostomia (dry mouth) and xerophthalmia (dry eyes). This syndrome may present as either a primary autoimmune disease or as a secondary autoimmune disease most often concomitant with other connective tissue diseases or diabetes. Although classified as an orphan disease, Sjogren's syndrome is grossly under-diagnosed; thus, it is estimated as many as 2-4 million individuals (90 percent of whom are women) actually have a form of this disease. At present, diagnosis of Sjogren's syndrome involves detection of lymphocytic infiltrates in biopsies of the labial glands; the presence of rheumatoid factor, serum antibodies reactive with cellular components (e.g., SS-A/Ro, SS-B/La, alpha-fodrin and/or nuclear factors), hypergamma-globulinemia, and loss of exocrine gland flow rates. None of these markers, by itself, is disease specific. Recently, we and others have shown that all sera from patients with confirmed Sjogren's syndrome contain antibody to the type-3 muscarinic acetylcholine receptor (M3R) expressed on exocrine tissues. This autoantigen, therefore, appears to be the single marker able to define autoimmune exocrinopathy. Work carried out under our Phase I grant has shown the feasibility of establishing an ELISA-based assay that utilizes a full-length recombinant form of human M3R to detect anti-M3R autoantibody in Sjogren's syndrome patients. Thus, the specific aims of this Phase II grant are to 1) complete the development of the ELISA-based assay, 2) obtain both analytical and clinical performance data for the ELISA-based assay, and 3) determine the precise association between the detection of anti-M3R autoantibody and prediction of disease in Sjogren's syndrome patients. Final development of a simple, non-surgical, Sjogren's syndrome-specific diagnostic test would be a welcome addition to the patient, the treating physician, and the clinical laboratory.