TRIGGERING ANTIGENS IN JUVENILE RHEUMATOID ARTHRITIS

幼年类风湿关节炎中的触发抗原

• 批准号: 2083720
• 负责人: BARBARA S NEPOM
• 金额: $ 21.48万
• 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/2083720
• 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.

少关节起病的幼年类风湿性关节炎(少关节JRA)是最多的 儿科风湿病的常见形式，占显著的 肌肉骨骼和眼部并发症的发病率。病因学 是未知的。我们和其他人已经阐明了显著的人类白细胞抗原关联 在这种情况下，这是唯一和复杂的：HL-DR8和DR5是 与疾病密切相关，DPB2.1赋予独立 易感性，而其他II类等位基因，如DR4似乎提供了 保护。T细胞受体使用有限的一些证据也是 正在浮现。然而，触发抗原仍然是一个关键因素 发病机制知之甚少的疾病。它的解释可能 提供最直接的方法来开发新的治疗或 预防策略。我们建议利用独创的分子方法 开始鉴定易感人群中引发少齿类JRA的抗原(S) 主持人。具体地说，我们将获得与DR8结合良好的多肽基序 和DR5，但不是DR4，使用分子建模和实验多肽 有约束力的分析。我们将利用这一主题来确定潜在的约束 从已知的候选触发抗原序列中提取多肽并进行检测 这些直接用于绑定。作为一种补充的、独立的方法，我们 将衍生出在Pauci JRA中表达的DR8和DR5结合肽 滑膜样本，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多肽与患者的反应性 滑膜T细胞。这个项目解决了我们在理解上的一个关键差距 一种知之甚少的疾病，并有可能为 新的治疗或预防策略。