Ig-Reactive T Cells in Rheumatoid Arthritis

类风湿关节炎中的 Ig 反应性 T 细胞

• 批准号: 6561896
• 负责人: RUSSELL D. SALTER
• 金额: $ 7.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-23 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6561896
• 关键词: MHC class II antigen; T lymphocyte; biomarker; clinical research; human subject; immunoglobulin G; isoantibody; leukocyte activation /transformation; osteoarthritis; patient oriented research; rheumatoid arthritis; rheumatoid factor

DESCRIPTION (provided by applicant): Between 70-80% of rheumatoid arthritis (RA) patients produce antibodies against IgG, called rheumatoid factors (RF), suggesting that IgG is a common auto-antigen in the disease. Although anti-IgG antibodies are present in other diseases and during immune responses to pathogens, these are generally low affinity IgMs that are detectable only transiently. In RA however, RF are persistent, usually of moderate to high affinity, and may include multiple isotypes. In addition, IgM RF can show evidence of somatic hypermutation. We therefore hypothesize that activation of T cells reactive with IgG could mediate affinity maturation and/or isotype switching in RF-producing B cells in at least a subset of RA patients. To address this, we have developed class II MHC tetramers containing peptides of Ig kappa chain that are shown to bind increased numbers of CD4+ T cells in some RA patients. In specific aim 1, we propose to determine how tetramer reactivity relates to expression of particular class II HLA proteins, including subtypes of HLA-DR4 shown previously to be associated with RA. In specific aim 2, we will test whether increased tetramer reactivity found in some patients correlates with the presence of multiple isotype rheumatoid factors, and with several markers, which can be used to measure disease severity. These experiments should critically assess the hypothesis that T cell help is required for production of multiple isotype RF, and may distinguish subsets of patients based on tetramer reactivity that have different prognoses, and who might benefit from distinct treatment regimens.

描述（由申请人提供）： 70-80%的类风湿性关节炎（RA）患者产生抗IgG抗体，称为类风湿因子（RF），表明IgG是该疾病中常见的自身抗原。虽然抗IgG抗体存在于其他疾病和对病原体的免疫应答过程中，但这些抗体通常是低亲和力的IgM，只能短暂检测到。然而，在RA中，RF是持久的，通常具有中等至高亲和力，并且可能包括多种同种型。此外，IgM RF可以显示体细胞高突变的证据。因此，我们假设，与IgG反应的T细胞的活化可以介导亲和力成熟和/或同种型转换的RF生产B细胞中至少一个子集的RA患者。为了解决这个问题，我们已经开发了II类MHC四聚体，其含有IG κ链的肽，其显示出在一些RA患者中结合增加数量的CD 4 + T细胞。在具体目标1中，我们提出确定四聚体反应性如何与特定II类HLA蛋白的表达相关，包括先前显示与RA相关的HLA-DR 4亚型。在具体目标2中，我们将测试在一些患者中发现的增加的四聚体反应性是否与多种同种型类风湿因子的存在相关，以及与可用于测量疾病严重程度的几种标志物相关。这些实验应该批判性地评估T细胞帮助产生多种同种型RF所需的假设，并且可以基于具有不同的四聚体反应性来区分患者的亚群，并且谁可能受益于不同的治疗方案。