Rheumatoid Arthritis: Progession /autoimmunity to diseas

类风湿性关节炎：疾病进展/自身免疫

• 批准号: 7197622
• 负责人: Vernon Michael Holers
• 金额: $ 124.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197622
• 关键词: autoimmune disorder; autoimmunity; biomarker; child (0-11); cooperative study; disease /disorder proneness /risk; early diagnosis; family genetics; gene environment interaction; genetic susceptibility; histocompatibility antigens; histocompatibility typing; human subject; pathologic process; patient oriented research; rheumatoid arthritis

The goal of this Project is to identify a subset of first-degree relatives (FDRs) of probands with rheumatoid arthritis (RA) who are currently asymptomatic but who demonstrate both genotypic and phenotypic characteristics that are highly predictive of the development of RA within 3-5 years. We believe that identifying and further characterizing this very high risk population is key to the future goal of developing a primary prevention strategy that would target those individuals for therapeutic intervention prior to the onset of clinically active RA. As part of a funded R01, over the next five years we will finish enrolling and fully evaluating 2100 FDRs of probands with RA. Based on preliminary data, we expect to find a substantial number of FDRs who exhibit patterns of RA-related autoantibodies associated with progression to RA but who do not yet have clinically active disease. From the probands as well as these FDRs, we will also obtain biologic samples that can be used for DNA and other biomarker analysis. We are funded in that R01 to perform RA-related autoantibody and HLA-DR shared epitope analysis, and to re-evaluate FDRs serially in order to follow clinical phenotypes and obtain serial biologic samples. Because of the study design, FDRs can also be readily stratified for the new studies we propose herein by clinical phenotype, RA shared epitope or other genotype, and autoantibody status. Based on additional preliminary data, we expect to find, using both cross sectional and serial analyses, that the RA-associated autoantibody positive FDR group can be further divided into a population that does not exhibit additional biomarkers that are very likely to be associated with progression to clinically active RA, and a population that does exhibit such features of progression. We also expect to find evidence of B and T cell dysfunction in unaffected FDRs who exhibit RArelated autoantibodies and will have a unique opportunity to detect pathogenic T cell epitopes. To accomplish these goals, we propose the following Specific Aims: Specific Aim #1: Determine the proportion of asymptomatic autoantibody-positive FDRs who also exhibit additional biomarkers typically found in patients with active RA. Specific Aim #2: Determine in asymptomatic FDRs the relationships of RA-related autoantibodies and biomarkers to the presence of specific genetic alleles and HLA haplotypes that are associated with the classification of active RA. Specific Aim #3: Examine FDRs who exhibit RA-related autoantibodies for the presence of dysregulated B and T cell immune responses to RA-related autoantigens.

该项目的目标是确定类风湿先证者的一级亲属 (FDR) 子集 目前无症状但同时表现出基因型和表型的关节炎 (RA) 高度预测 3-5 年内 RA 发展的特征。我们相信 识别并进一步描述这一高危人群的特征是制定未来目标的关键 一级预防策略，在发病前针对这些个体进行治疗干预 临床活动性 RA。作为资助的 R01 的一部分，我们将在未来五年内完成注册并全面 评估 2100 名 RA 先证者的 FDR。根据初步数据，我们预计将发现大量 表现出与 RA 进展相关的 RA 相关自身抗体模式的 FDR 数量，但 尚未患有临床活动性疾病的人。从先证者以及这些 FDR 中，我们还将获得 可用于 DNA 和其他生物标志物分析的生物样品。我们通过 R01 获得资助 执行 RA 相关自身抗体和 HLA-DR 共享表位分析，并连续重新评估 FDR 为了跟踪临床表型并获得系列生物样本。由于研究设计，FDR 也可以很容易地根据临床表型、RA 共享表位对我们在此提出的新研究进行分层 或其他基因型，以及自身抗体状态。根据额外的初步数据，我们期望发现，使用 横断面分析和系列分析表明，RA 相关自身抗体阳性 FDR 组可以 进一步分为不表现出额外生物标志物的群体，这些生物标志物很可能是 与进展为临床活动性 RA 相关，以及确实表现出此类特征的人群 进展。我们还期望在表现出 RA 相关性的未受影响的 FDR 中找到 B 和 T 细胞功能障碍的证据 自身抗体，并将有独特的机会检测致病性 T 细胞表位。到 为了实现这些目标，我们提出以下具体目标： 具体目标#1：确定也表现出无症状自身抗体阳性 FDR 的比例 通常在活动性 RA 患者中发现的其他生物标志物。 具体目标 #2：确定无症状 FDR 中 RA 相关自身抗体与 与特定遗传等位基因和 HLA 单倍型存在相关的生物标志物 活动性 RA 的分类。 具体目标#3：检查表现出 RA 相关自身抗体的 FDR 是否存在失调的 B 和 T 细胞对 RA 相关自身抗原的免疫反应。