ROLE OF CYTOKINES IN RHEUMATOID ARTHRITIS

类风湿关节炎(RA)是一种自身免疫性疾病，其特征是T细胞和抗原提呈细胞(APC)从血液中渗入滑膜关节。这两种细胞类型的激活都会导致关节内组织的破坏。这种组织破坏导致大量的自身蛋白质可供吞噬细胞APC摄取。自体多肽的呈递：APC的MHC复合体被认为能激活和扩增自身反应性T细胞。最有说服力的证据表明抗原提呈在类风湿性关节炎中的作用是观察到，某些亚型的人类白细胞抗原-DR4等位基因的遗传使人们易于发生类风湿性关节炎。这些DR4亚型所呈现的自体多肽的性质目前尚不清楚，但在动物模型中进行的研究已经提供了一些候选的自身抗原。建议进行以下研究：目的1：确定正常外周血APC表达的候选自身抗原衍生的表位阵列，并确定细胞因子如何调节这些表位的呈递；目的2：确定RA患者APC表达的候选自身抗原衍生的表位阵列，并确定细胞因子如何调节这些表位的呈递；目的3：确定从类风湿滑膜获得的成熟树突状细胞是否由于炎性细胞因子的存在而显示出处理和呈递可溶性自身抗原的能力增强。用这些候选自身抗原免疫人DR4转基因小鼠，获得了识别DR4背景下的人II型胶原、HCgp39和钙网织蛋白多肽的T细胞杂交瘤。这些T细胞杂交瘤可以用来研究患有和不患有类风湿关节炎的人DR4捐赠者的APC对这些表位的呈递。

Rheumatoid arthritis (RA) is an autoimmune disease characterized by infiltration of T cells and antigen presenting cells (APC) from the blood into the synovial joint. Activation of both cell types results in destruction of tissue within the joint. This tissue destruction leads to an abundance of self proteins available for uptake by phagocytic APC. Presentation of self peptide:MHC complexes by APC is believed to lead to activation and expansion of autoreactive T cells. The most convincing evidence implicating a role for antigen presentation in RA is the observation that inheritance of certain subtypes of the HLA-DR4 allele predisposes people to developing RA. The nature of the self peptides being presented by these DR4 subtypes is currently not known, but studies performed in animal models have provided some candidate autoantigens. The following studies are proposed: Aim 1: Determine the array of epitopes derived from candidate autoantigens expressed by normal peripheral blood APC and determine how cytokines modulate presentation of these epitopes; Aim 2: Determine the array of epitopes derived from candidate autoantigens expressed by APC obtained from RA patients and determine how cytokines modulate presentation of these epitopes; Aim 3: Determine if mature dendritic cells obtained from rheumatoid synovia display enhanced ability to process and present soluble autoantigens due to the presence of inflammatory cytokines. T cell hybridomas which recognize peptides derived from human type II collagen HCgp39 and calreticulin in the context of DR4 have been generated by immunizing human DR4 transgenic mice with these candidate autoantigens. These T cell hybridomas can then be used to study presentation of these epitopes by APC from human DR4 donors with and without rheumatoid arthritis.