ROLE OF RHEUMATOID FACTOR IN IMMUNOREGULATION

在人类中，类风湿因子（RF）产生的增加与 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攻击。 是 假设RF导致淋巴细胞过度活跃， 类风湿关节炎的炎症特征与持续抗体的调节 正常人的反应。 这个假设是建立在 RF识别自体IgG;因此RF可能有助于形成 生物活性免疫复合物（IC）或结合到表面 免疫球蛋白对B细胞的调节作用。 这个的目标 建议是调查的机制，其中：i）射频相关的IC （RF-IC）体外多克隆活化人B细胞; ii）RF-IC诱导 培养的人单核细胞以产生花生四烯酸（AA） 代谢物，其中一些可能作为炎症介质和/或 免疫调节分子;和iii）单克隆RF，不含IC，调节 有丝分裂原和抗原诱导的人体外抗体应答。 实验将在培养的人外周血中进行 来自自身免疫患者和正常受试者的单核细胞， 以确定对RF-IC和RF的反应性的疾病特异性模式。 初步数据表明，从RA患者血浆中分离的RF-IC 患者，能够多克隆激活正常人B细胞并诱导 体外正常单核细胞AA代谢产物的释放。 因此，将进行研究以物理表征RF-IC 从各种来源（血浆，滑液），并确定细胞 以及B细胞活化和AA代谢物释放的亚细胞参数 在这些准备工作中。 其他初步数据显示， 单克隆人IgM RF能够抑制抗原， 正常人淋巴细胞培养物中丝裂原诱导的抗体应答。 因此，将生产一组单克隆IgM RF，对其进行表征， 并评估对体外抗体的刺激和抑制作用 应答 将开展研究，探讨 这些制剂调节B细胞功能。

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.