Ig-Reactive T Cells in Rheumatoid Arthritis

描述(由申请人提供)： 70%-80%的类风湿性关节炎(RA)患者会产生针对IgG的抗体，称为类风湿因子(RF)，这表明IgG是疾病中常见的自身抗原。虽然在其他疾病和对病原体的免疫反应中也存在抗-Ig G抗体，但这些抗体通常是低亲和力的Ig M，只能瞬时检测到。然而，在RA中，RF是持久的，通常具有中等到高的亲和力，并且可能包括多种同功型。此外，IgM RF还可以显示体细胞超突变的证据。因此，我们假设，在至少一部分RA患者中，T细胞与免疫球蛋白反应的激活可以调节产生RF的B细胞的亲和力成熟和/或同型转换。为了解决这个问题，我们开发了包含Ig kappa链的多肽的II类MHC四聚体，这些多肽被证明可以结合一些RA患者中数量增加的CD4+T细胞。在特定的目标1中，我们建议确定四聚体反应性如何与特定的II类HLA蛋白的表达有关，包括先前被证明与RA相关的HLA-DR4亚型。在特定目标2中，我们将测试在一些患者中发现的四聚体反应性增加是否与多种同型类风湿因子的存在以及几个可用于衡量疾病严重程度的标记物相关。这些实验应该批判性地评估T细胞帮助产生多个同型RF的假设，并可能基于四聚体反应区分具有不同预后的患者亚群，以及谁可能从不同的治疗方案中受益。

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.