TRIGGERING ANTIGENS IN JUVENILE RHEUMATOID ARTHRITIS

幼年类风湿关节炎中的触发抗原

• 批准号: 2769638
• 负责人: BARBARA S NEPOM
• 金额: $ 22.15万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2769638
• 关键词: T cell receptor; adolescence (12-20); alleles; antigen presentation; antigen presenting cell; autoantigens; binding proteins; child (0-11); enzyme linked immunosorbent assay; flow cytometry; gene expression; gene induction /repression; histocompatibility antigens; human genetic material tag; human subject; immune response genes; immunogenetics; juvenile rheumatoid arthritis; nucleic acid sequence; pathologic process; peptide structure; polymerase chain reaction; receptor binding; site directed mutagenesis; synovial fluid

Pauciarticular onset juvenile rheumatoid arthritis (pauci JRA) is the most common form of pediatric rheumatic disease, and accounts for significant morbidity from both musculoskeletal and ocular complications. The etiology is unknown. We and others have elucidated the striking HLA associations with this condition, which are unique and complex: HLA-DR8 and DR5 are strongly associated with disease, and DPB2.1 confers independent susceptibility, while other class II alleles such as DR4 appear to provide protection. Some evidence of limited T cell receptor usage is also emerging. The triggering antigen, however, remains a crucial factor in disease pathogenesis about which very little is known. Its elucidation may provide the most direct means of developing novel therapeutic or prevention strategies. We propose to utilize original molecular approaches to begin to identify the antigen(s) triggering pauci JRA in susceptible hosts. Specifically, we will derive peptide motifs which bind well to DR8 and DR5, but not to DR4, using molecular modeling and experimental peptide binding assays. We will utilize that motif to identify potential binding peptides from known sequences of candidate triggering antigens and test these directly for binding. As a complementary, independent approach, we will derive DR8 and DR5 binding peptides that are expressed in pauci JRA synovial samples, using a novel molecular expression approach. Finally, we will test these derived peptides directly for reactivity with patient synovial T cells. This project tackles a critical gap in our understanding of a poorly understood disease, and potentially will provide the basis for novel therapeutic or preventive strategies.

少关节型幼年型类风湿关节炎（少关节型JRA）是最常见的类风湿性关节炎。 小儿风湿性疾病的常见形式，并占显着 肌肉骨骼和眼部并发症。病因 不明我们和其他人已经阐明了显著的HLA关联 与这种情况，这是独特的和复杂的：HLA-DR 8和DR 5是 与疾病密切相关，DPB 2.1赋予独立的 易感性，而其他II类等位基因如DR 4似乎提供了 保护也有一些证据表明，T细胞受体的使用有限， 正在浮现然而，触发抗原仍然是 疾病的发病机制，其中知之甚少。其说明可 提供开发新的治疗或 预防战略。我们建议利用原始的分子方法 开始鉴定易感人群中触发少JRA的抗原 hosts.具体而言，我们将获得与DR 8结合良好的肽基序 和DR 5，但不是DR 4，使用分子建模和实验肽 结合测定。我们将利用该基序来识别潜在的结合 来自候选触发抗原的已知序列的肽和测试 这些直接用于绑定。作为一种独立的、互补的方法，我们 将衍生在pauci JRA中表达的DR 8和DR 5结合肽， 滑膜样品，使用一种新的分子表达方法。最后我们 将直接测试这些衍生肽与患者的反应性 滑膜T细胞这个项目解决了我们理解的一个关键差距 一种知之甚少的疾病，并可能为 新的治疗或预防策略。