Role of T Cells Specific for Citrullinated Fibrinogen in Rheumatoid Arthritis

 描述（由申请人提供）：风湿性关节炎（RA）是一种自身免疫性疾病，被认为主要由细胞因子和抗体介导，但我们对这种疾病的免疫学事件的理解存在重要差距。对瓜氨酸化自身抗原的细胞和高亲和力体液自身免疫应答的关键作用的新认识使这些免疫机制在RA发病机制中的重要性得到新的强调。我们在该试点项目中解决的一个关键问题涉及CD4 T细胞对瓜氨酸化自身抗原的反应，这些抗原驱动疾病的最早过程，以及这些反应如何与这些抗原的自身抗体的存在相关。 我们最近研究了瓜氨酸化纤维蛋白原（CF），一种自身抗原，RA患者对其产生大量类别转换IgG体液免疫应答，作为RA小鼠模型中B细胞和CD4 T细胞的自身抗原。我们开发了小鼠模型，其中单克隆抗瓜氨酸蛋白抗体（ACPA）或对瓜氨酸纤维蛋白原有反应的T细胞系可用于加重体内疾病。我们在这个试点项目提案中的主要目标是研究CF特异性CD4 T细胞如何促进疾病过程并与ACPA相互作用，导致关节特异性损伤的发展。我们的中心假设是，从疾病的临床前抗体阶段到临床关节炎的转变是关节中瓜氨酸化自身抗原形成后的两次打击过程，并且与瓜氨酸化蛋白反应的抗体和T细胞都有助于发病机制。我们的第一个目的是研究对CF反应的CD4 T细胞的致病潜力以及抗CF CD4 T细胞在RA小鼠模型中加重疾病的机制。为了实现这些目标，我们将研究CF特异性的CD4 T细胞系如何在体内发挥作用，并确定抗CF系是否可以单独或仅与抗原免疫结合诱导关节炎。在第二个目标下，我们将研究ACPA是否可以通过与致病性CD4 T细胞的协同作用促进RA的发病机制，以及该过程是否需要开发先天免疫驱动的瓜氨酸化靶抗原的局部产生。 我们提出的研究的意义在于它们可能产生关于RA发展的基本自身免疫过程的新信息。这些信息可能对建立新的疾病生物标志物和治疗干预靶点具有重要意义。

 DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an autoimmune disease considered to be primarily mediated by cytokines and antibodies, but there are important gaps in our understanding about the immunological events underlying this disease. The emerging understanding of the key role of cellular and high affinity humoral autoimmune responses to citrullinated autoantigens lends new emphasis to the importance of these immune mechanisms in the pathogenesis of RA. A critical question that we address in this pilot project pertains to th CD4 T cell response to the citrullinated autoantigens that drive the earliest processes of the disease and how these responses are linked to the presence of autoantibodies to these antigens. We have recently investigated citrullinated fibrinogen (CF), an autoantigen to which a substantial class-switched IgG humoral immune response is generated in patients with RA, as an autoantigen for both B cells and CD4 T cells in a mouse model of RA. We have developed mouse models in which monoclonal anti-citrullinated protein antibodies (ACPAs) or T cell lines reactive to citrullinated fibrinogen can be used to exacerbate disease in vivo. Our main objective in this pilot project proposal is to investigate how CD4 T cells specific for CF contribute to the disease process and interact with ACPAs to result in the development of joint-specific damage. Our central hypothesis is that the transition from the preclinical antibody phase of disease to clinical arthritis is a two-hit process following the formation of citrullinated autoantigens in th joint and that both antibodies and T cells reactive to citrullinated proteins contribute to pathogenesis. Our first aim is to investigate the pathogenic potential of CD4 T cells reactive to CF and the mechanisms by which anti-CF CD4 T cells exacerbate disease in a mouse model of RA. To achieve these goals we will examine how CD4 T cell lines specific for CF function in vivo and determine whether the anti-CF line can induce arthritis alone or only in combination with antigen immunization. Under the second aim, we will investigate whether ACPAs can contribute to pathogenesis of RA through synergy with pathogenic CD4 T cells and whether this process requires the development of innate-immune driven local generation of citrullinated target antigens. The significance of our proposed studies lies in the new information they may generate with regard to the basic autoimmune processes by which RA develops. Such information could have important implications for establishing new biomarkers of disease and targets for therapeutic intervention.