M3 RECEPTOR: DIAGNOSTIC MARKER FOR SJOGREN'S SYNDROME

M3 受体：干燥综合征的诊断标志物

• 批准号: 6135024
• 负责人: MICHAEL G HUMPHREYS-BEHER
• 金额: $ 10万
• 依托单位: IXION BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6135024
• 关键词: autoantibody; autoimmune disorder; biomarker; cell line; clinical research; diagnosis design /evaluation; diagnostic tests; enzyme linked immunosorbent assay; female; human subject; immunopathology diagnosis; lacrimal disorder; mucus; salivary disorder; transfection; xerophthalmias; xerostomias

Sjogren's syndrome is a human autoimmune disease of the salivary and lacrimal glands resultIng in debilitating xerostomia (dry mouth) and xerophthalmia (dry eyes). This disease may present as either a primary autoimmune disease or as a secondary autoimmune disease concomitant with other connective tissue diseases or diabetes. Although classified as an orphan disease, it is grossly under-diagnosed; thus, it is estimated that as many as 2-4 million individuals (90% of which are women) actually have a form of the disease. At present, diagnosis of Sjogren's syndrome involves detection of lymphocytic infiltrates in biopsies of the labial glands, the presence of autoantibodies to rheumatoid factor and cellular components (e.g., SS-A/Ro, SS-B/La, alpha-fodrin and nuclear material), hypergammaglobulinemia, and loss of exocrine gland flow rates following stimulation. None of these markers is, by itself, disease specific. Recently, we and others have shown that all sera from patients with confirmed Sjogren's syndrome contain an autoantibody to the muscarinic cholinergic-3 receptors (M3) expressed on exocrine gland cells. This finding presents the possibility that this single marker may be able to define autoimmune exocrinopathy. Thus, we propose to investigate the feasibility of developing a simple, non-invasive diagnostic test capable of identifying patients with Sjogren's syndrome. Specific aims of this phase STTR grant are i) to determine if Sjogren's syndrome patients can be identified specifically and universally with an ELISA test using a full-length recombinant form of the M3 protein, and 2) compare the results from ELISA testing with those obtained utilizing a M3-expressing, transfected COS-7 cell line. If results of this study confirm and expand our preliminary data, then final development of a simple, non-invasive, Sjogren's syndrome-specific diagnostic test would be a welcome addition to the clinical diagnostic laboratory and the patient. PROPOSED COMMERCIAL APPLICATIONS: Identification of autoantibodies against the muscarinic acetylcholine-3 receptor (M3) on exocrine gland cells now appears to be the best single marker of autoimmunity in Sjogren's syndrome (autoimmune exocrinopathy). While Sjogren's syndrome is classified an orphan disease, it is also recognized as being under-diagnosed; thus, there may be perhaps 2-4 million patients in the US, 90% of which are women. Development of a non-invasive diagnostic test based on detection of M3 autoantibody would be a major advancement for the clinical laboratory.

干燥综合征是一种人类唾液腺和泪腺的自身免疫性疾病，导致使人衰弱的口干症（口干）和干眼症（干眼症）。这种疾病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伴发其他结缔组织疾病或糖尿病。虽然被归类为孤儿病，但诊断严重不足;因此，据估计，多达200万至400万人（其中90%是妇女）实际上患有某种形式的疾病。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、类风湿因子和细胞成分（例如，SS-A/Ro、SS-B/La、α-胞衬蛋白和核物质）、高丙种球蛋白血症和刺激后外分泌腺流速丧失。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一种自身抗体的毒蕈碱胆碱能受体3（M3）表达的外分泌腺细胞。这一发现提出了这种单一标记物可能能够定义自身免疫性外分泌蛋白病的可能性。因此，我们建议研究开发一种简单的，非侵入性的诊断测试能够识别干燥综合征患者的可行性。该阶段STTR资助的具体目标是：i）确定是否可以使用全长重组形式的M3蛋白通过ELISA检测特异性和普遍性地鉴定干燥综合征患者，以及2）将ELISA检测的结果与使用表达M3的转染COS-7细胞系获得的结果进行比较。如果这项研究的结果证实并扩展了我们的初步数据，那么最终开发出一种简单的、非侵入性的、干燥综合征特异性诊断测试将是临床诊断实验室和患者的一个受欢迎的补充。拟议的商业应用：现在，针对外分泌腺细胞上的毒蕈碱乙酰胆碱-3受体（M3）的自身抗体的鉴定似乎是干燥综合征（自身免疫性外分泌病）中自身免疫的最佳单一标志物。虽然干燥综合征被归类为孤儿疾病，但它也被认为是诊断不足;因此，在美国可能有2 - 4百万患者，其中90%是女性。基于M3自身抗体检测的非侵入性诊断测试的开发将是临床实验室的重大进步。