Role of T Cells Specific for Citrullinated Fibrinogen in Rheumatoid Arthritis

 描述(申请人提供)：类风湿性关节炎(RA)是一种被认为主要由细胞因子和抗体介导的自身免疫性疾病，但我们对该疾病背后的免疫学事件的理解存在重大差距。随着对瓜氨酸自身抗原的细胞和高亲和力体液自身免疫反应的关键作用的逐渐认识，这些免疫机制在RA发病机制中的重要性得到了新的强调。我们在这个试点项目中解决的一个关键问题与CD4T细胞对驱动疾病最早过程的瓜氨酸自身抗原的反应有关，以及这些反应如何与针对这些抗原的自身抗体的存在有关。我们最近在RA小鼠模型中研究了瓜氨酸纤维蛋白原(CF)作为B细胞和CD4T细胞的自身抗原，这是一种自身抗原，在RA患者中对其产生实质性的类别转换免疫应答。我们已经建立了小鼠模型，在这些模型中，抗瓜氨酸蛋白抗体(ACPA)或对瓜氨酸化纤维蛋白原起反应的T细胞系可以用来在体内加重疾病。我们在这个试点项目提案中的主要目标是研究针对CF的CD4T细胞如何在疾病过程中起作用，并与ACPA相互作用，导致关节特异性损伤的发生。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在关节中形成瓜氨酸自身抗原之后的两次打击过程，对瓜氨酸蛋白起反应的抗体和T细胞都参与了发病。我们的第一个目标是研究CD4T细胞对CF的致病潜能，以及抗CFCD4T细胞在RA小鼠模型中加重疾病的机制。为了实现这些目标，我们将研究针对CF的CD4T细胞系在体内是如何发挥作用的，并确定抗CF系是否可以单独或仅与抗原免疫联合诱导关节炎。在第二个目标下，我们将研究ACPA是否通过与致病的CD4T细胞协同作用而促进RA的发病，以及这一过程是否需要天然免疫驱动的局部产生瓜氨酸靶抗原。我们建议的研究的意义在于它们可能产生关于RA发生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记物和治疗干预目标具有重要意义。

 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.