CR1 AND FCYRIIA/IIIA DEFECTS IN THE PATHOGENESIS OF SLE

SLE 发病机制中的 CR1 和 FCYRIIA/IIIA 缺陷

• 批准号: 6137225
• 负责人: DANIEL J BIRMINGHAM
• 金额: $ 17.96万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2001-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137225
• 关键词: CD antigens; CD16 molecule; biomarker; clinical research; complement receptor; gene environment interaction; gene frequency; gene mutation; genetic mapping; genetic polymorphism; genetic susceptibility; human subject; immune complex; receptor binding; relapse /recurrence; systemic lupus erythematosus

The long-term goal of this research is to define the environmental and genetic influences that lead to the development of SLE and to disease manifestation. Because the classic lesion in SLE is immune complex (IC) driven tissue inflammation, we believe that these influences are, in part, defects in IC clearance receptors, namely erythrocyte type on complement receptor (E-CR1). Studies indicate that specific defects in CR1 occur in SLE. It is not known if these defects are genetic in nature or are acquired during disease, or whether these defects can affect or predict disease severity. In support of genetic defects, we have recently identified 7 CR1 mutations, 6 which appear to segregate with SLE or normals, and one which may be associated with low E-CR1 levels. Three mutations appear to affect ligand binding. The goal of this proposal is determine the extent that these mutations affect CR1 function, and to establish if these mutations, with or without combinations of dysfunctional FcgammaRIIa/FcgammaRIIIa variants, are associated with SLE. This study will also seek to determine if acquired E-CR1 defects preclude SLE relapse or are associated with disease manifestation. Accordingly, the aims of this project are to: 1) Characterize E-CR1 phenotypes at study entry in a large cohort of normals and SLE patients, 2) Map the seven known mutation for CR1 in the normals and SLE patients to determine relative frequencies, 3) Express and characterize the CR1 patients variants, 4) Map two known FcgammaR variants known to be associated with SLE, and 5) Assess changes in E-CR1 in SLE patients during periods of relapse and remission. E-CR1 will be characterized in 144 SLE patients and 144 normals. Leukocyte cDNA for specific regions of CR1, FcgammaRIIa, and FcgammaRIIIa will be amplified, and the frequency of known mutations will be identified to determine if any polymorphic variant or combination of variants are associated with SLE. The CR1 polymorphisms will be expressed in truncated CR1 constructs to determine the affects on specific functional domains, and this data will be compared to the E-CR1 characterization to assess mutation effects in the intact CR1 molecule. Finally, E-CR1 will be characterized in 50 SLE patients at bi-monthly intervals to determine if E-CR1 defects preclude, and thus predict, SLE relapse, or are associated with specific disease manifestations. The results of the proposed studies should clarify the roles that both genetic and acquired defects in CR1 play in the onset and disease manifestation of SLE.

这项研究的长期目标是定义环境和 导致系统性红斑狼疮和疾病的遗传影响 显化。因为系统性红斑狼疮的典型病变是免疫复合物(IC) 驱动组织炎症，我们认为这些影响是，在 部分，IC清除受体缺陷，即红细胞型 补体受体(E-CR1)。研究表明，特定的缺陷 CR1多见于SLE。目前尚不清楚这些缺陷是否是遗传性的 自然或在疾病中获得的，或者这些缺陷是否可以 影响或预测疾病的严重性。为了支持基因缺陷，我们 最近发现了7个CR1突变，其中6个似乎是分离的 有SLE或正常的，以及可能与E-CR1低相关的 级别。三个突变似乎会影响配基结合。的目标是 这一建议决定了这些突变对CR1的影响程度 功能，并确定这些突变，无论有没有 功能失调的FcGammaRIIa/FcGammaRIIa变体的组合是 与系统性红斑狼疮相关。这项研究还将寻求确定是否获得了 E-CR1缺陷可防止SLE复发或与疾病相关 显化。因此，本项目的目标是：1) 在研究开始时对E-CR1表型进行表征 正常人和SLE患者，2)将CR1的七个已知突变映射到 确定正常人和SLE患者的相对频率，3)Express 和CR1患者变种的特征，4)映射两个已知的FcGammaR 已知与系统性红斑狼疮相关的变异，以及5)评估E-CR1的变化 在SLE患者的复发和缓解期。 144名SLE患者和144名正常人将以E-CR1为特征。 CR1、FcGammaRIIa和FcGammaRIIa特定区域的白细胞基因 FcGammaRIIIa将被扩增，已知突变的频率 将被识别以确定是否有任何多态变体或 变异的组合与系统性红斑狼疮相关。CR1基因的多态性 将在截断的CR1构造中表达以确定影响 在特定的功能领域，这些数据将与 E-CR1特性用于评估完整CR1的突变效应 分子。最后，50名系统性红斑狼疮患者的E-CR1将在 每隔两个月确定E-CR1缺陷是否排除，从而 预测、SLE复发，或与特定疾病相关 表现形式。建议的研究结果应能澄清 CR1基因缺陷和获得性缺陷在发病中的作用 SLE的疾病表现。