M3 Receptor--Diagnostic Marker for Sjogren's Syndrome

描述(申请人提供)：干燥综合征是一种人类唾液和泪腺的自身免疫性疾病，导致口干症(口腔干燥)和干眼症(眼睛干燥)。这种综合征可能是一种原发自身免疫性疾病，也可能是一种继发性自身免疫性疾病，通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，但干燥综合征被严重低估；因此，据估计，多达200-400万人(其中90%是妇女)实际上患有这种疾病。目前，干燥综合征的诊断包括在唇腺活检组织中检测淋巴细胞渗入、类风湿因子的存在、与细胞成分(如SS-A/Ro、SS-B/La、α-fodrin和/或核因子)反应的血清抗体、高丙种球蛋白血症和外分泌腺流速丧失。这些标记物本身都不是疾病特异性的。最近，我们和其他人发现，所有确诊的干燥综合征患者的血清中都含有外分泌组织表达的3型M胆碱受体(M3R)抗体。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记物。我们在第一阶段资助下开展的工作表明，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M3R来检测干燥综合征患者的抗M3R自身抗体。因此，这笔第二阶段赠款的具体目标是：1)完成基于酶联免疫吸附试验的开发；2)获得基于酶联免疫吸附试验的分析和临床表现数据；3)确定抗M3R自身抗体的检测与干燥综合征患者疾病预测之间的准确联系。最终开发一种简单的、非手术的、干燥综合征特异性诊断测试将是患者、治疗医生和临床实验室的一个受欢迎的补充。

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.