THE ROLE OF RHEUMATOID FACTOR IN IMMUNOREGULATION

在人类中，类风湿因子(RF)的产生增加与 患有类风湿性关节炎(RA)和其他自身免疫现象，慢性 病毒和细菌感染，以及二次抗原挑战。它是 假设RF有助于淋巴细胞过度活跃和 类风湿关节炎的炎症特征与持续抗体的调节 正常受试者的反应。这一假说建立在以下能力之上 Rf识别自体免疫球蛋白；因此Rf可能有助于形成 生物活性免疫复合体(IC)或与表面结合 B细胞上的免疫球蛋白具有调节作用。这样做的目的是 提案的目的是研究以下机制：i)射频相关集成电路 (RF-IC)多克隆体外激活人B细胞；II)RF-IC诱导 培养人单核细胞产生花生四烯酸(AA) 代谢物，其中一些可能起到炎症介质和/或 免疫调节分子；以及iii)不含IC的单克隆性RF调节 有丝分裂原和抗原诱导的人体体外抗体反应。 实验将在培养的人外周血上进行 自身免疫性疾病患者和正常人的单个核细胞 以确定对RF-IC和RF的疾病特异性反应模式。 初步数据显示，从RA患者血浆中分离到的RF-IC 患者能够多克隆地激活正常人类B细胞并诱导 正常单核细胞体外释放AA代谢物。 因此，将开展RF-IC的物理特性研究 从各种来源(血浆、滑液)中检测细胞 B细胞活化和AA代谢物释放的亚细胞参数 在有这些准备的情况下。其他初步数据显示 单克隆人IgM RF能够抑制抗原-和 正常人淋巴细胞培养中丝裂原诱导的抗体反应。 因此，将生产一组单抗IgM RF，并对其进行鉴定， 并评估对体外抗体的刺激和抑制作用 回应。将开始研究，以解决通过什么机制 这些制剂调节B细胞的功能。

In humans, increases in rheumatoid factor (RF) production are associated with rheumatoid arthritis (RA) and other autoimmune phenomena, chronic viral and bacterial infections, and secondary antigen challenge. It is hypothesized that RF contribute to the lymphocyte hyperactivity and inflammation characteristic of RA and the regulation of ongoing antibody responses in normal subjects. This hypothesis is founded on the ability of RF to recognize autologous IgG; thus RF could contribute to the formation of biologically-active immune complexes (IC) or bind to surface immunoglobulin on B cells with regulatory consequences. The goals of this proposal are to investigate the mechanisms by which: i) RF-associated IC (RF-IC) polyclonally activate human B cells in vitro; ii) RF-IC induce cultured human mononuclear cells to produce arachidonic acid (AA) metabolites, some of which may function as inflammatory mediators and/or immunoregulatory molecules; and iii) monoclonal RF, free of IC, regulate mitogen- and antigen-induced human in vitro antibody responses. Experiments will be performed on cultured human peripheral blood mononuclear cells from both autoimmune patients and normal subjects in order to identify disease-specific patterns of reactivity to RF-IC and RF. Preliminary data suggest that RF-IC, isolated from the plasma of RA patients, are able to polyclonally activate normal human B cells and induce the release of AA metabolites from normal mononuclear cells in vitro. Therefore, studies will be carried out to physically characterize RF-IC from various sources (plasma, synovial fluid) and determine the cellular and subcellular parameters of B cell activation and AA metabolite release in the presence of these preparations. Other preliminary data indicate that a monoclonal human IgM RF is able to inhibit antigen- and mitogen-induced antibody responses in normal human lymphocyte cultures. Therefore, a panel of monoclonal IgM RF will be produced, characterized, and assessed for stimulatory and inhibitory effects on in vitro antibody responses. Studies will be initiated to address the mechanism by which these preparations regulate B cell function.