M3 Receptor--Diagnostic Marker for Sjogren's Syndrome

描述（由申请人提供）：干燥综合征是一种唾液腺和泪腺的人类自身免疫性疾病，可导致使人衰弱的口干症（口干）和干眼症（干眼症）。 这种综合征可以表现为原发性自身免疫性疾病，也可以表现为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。 虽然被归类为孤儿疾病，但干燥综合征的诊断严重不足;因此，估计多达2-4百万人（其中90%是女性）实际上患有这种疾病。 目前，干燥综合征的诊断包括唇腺活检中淋巴细胞浸润的检测;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-胞衬蛋白和/或核因子）、高γ-球蛋白血症和外分泌腺流速丧失。 这些标记本身都不是疾病特异性的。 最近，我们和其他人已经表明，所有确诊的干燥综合征患者的血清含有抗体的3型毒蕈碱乙酰胆碱受体（M3 R）表达的外分泌组织。 因此，这种自身抗原似乎是能够定义自身免疫性外分泌病的单一标志物。 在我们的I期资助下进行的工作表明，建立一种基于ELISA的检测方法是可行的，该方法利用全长重组形式的人M3 R来检测干燥综合征患者中的抗M3 R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，以及3）确定抗M3 R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。 最终开发出一种简单的、非手术的、干燥综合征特异性的诊断试验，将是对患者、治疗医生和临床实验室的一个欢迎。

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.