RHEUMATOID FACTOR--GENETICS, PATHOGENESIS AND MODULATION

类风湿因子——遗传学、发病机制和调节

• 批准号: 2078544
• 负责人: DENNIS CARSON
• 金额: $ 24.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-15 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2078544
• 关键词: B lymphocyte; Epstein Barr virus; antibody formation; autoantibody; autoimmune disorder; histocompatibility antigens; human subject; hybridomas; immune complex; immunoglobulin genes; immunoglobulin idiotypes; laboratory mouse; laboratory rabbit; monoclonal antibody; radioimmunoassay; rheumatoid arthritis; rheumatoid factor; synovial fluid

Rheumatoid arthritis is a chronic inflammatory disease that primarily affects the joints. IgM and IgG autoantibodies reactive with the Fc fragment of IgG (rheumatoid factors, RF) are the hallmark of the disease. Understanding the structural and genetic basis for RF synthesis, and the reasons for sustained RF production in rheumatoid arthritis, is the long term objective of this research grant proposal. We have characterized antibodies that identify both variable region subgroups, and cross-reactive idiotypes (CRIs) on RFs, and have demonstrated that the light chains on monoclonal RFs from unrelated people are structurally related. Two V kappa genes (Humkv325 and Humkv328) that can encode human RF light chains were isolated and sequenced. The Humkv325 gene is utilized repeated in chronic lymphocytic leukemia, a lymphoproliferative disease that is often associated with autoantibody production. Other experiments revealed that IgM RF precursors are abundant in the blood and bone marrow of normal people, despite the absence of overt RF synthesis. Transient expansion of the IgM RF precursor cell pool regularly accompanies anamnestic immune responses. In rheumatoid arthritis, therefore, it is aberrant regulation of RF synthesis and diversification that is fundamental to the disease process, rather than the mere presence of the autoantibody. The proposed experiments intend to determine the causes of the abnormal regulation and to devise methods to overcome it. The specific aims of the experiments are: (1) to define the structural and genetic basis for three distinct CRIs on human monoclonal RF heavy chains; (2) to characterize the idiotypes and genes used for polyclonal RF synthesis in the blood and synovium of patients with rheumatoid arthritis; (3) to clarify the physiologic function of the RF CRI precursor B cells, by studying their distribution in lymphoid organs, their utilization in antibody responses against exogenous antigens, and their role in the processing of antigen-antibody complexes; (4) to discern how the HLA DR antigens Dw4 and DR1 may predispose to abnormally sustained RF production following exposure to an environmental antigen (Epstein-Barr virus gp110) that reproduces the rheumatoid arthritis susceptibility determinant in the DR beta-1 chain; and (5) to develop therapies that can prevent or terminate RF autoantibody production in experimental animals, and eventually in patients with rheumatoid arthritis and other RF-associated illnesses.

类风湿关节炎是一种慢性炎症性疾病，主要 影响关节。与Fc反应的IgM和Ig G自身抗体 免疫球蛋白片段(类风湿因子，RF)是该病的标志。 了解射频合成的结构和遗传基础，以及 类风湿关节炎持续产生RF的原因，是长期的 这项研究资助提案的学期目标。我们已经刻画了 识别可变区亚群和交叉反应的抗体 RFS上的独特型(CRI)，并证明了轻链上的 来自无关人群的单克隆性RFs在结构上是相关的。两个V卡帕 能够编码人类RF轻链的基因(Humkv325和Humkv328)是 分离并测序。Humkv325基因在慢性阻塞性肺疾病中的重复利用 淋巴细胞性白血病是一种淋巴增生性疾病，通常 与自身抗体的产生有关。其他实验表明， 正常人血液和骨髓中有丰富的IgM-RF前体 人们，尽管没有公开的射频合成。瞬时膨胀 免疫球蛋白M型RF前体细胞池经常伴随有记忆免疫 回应。因此，在类风湿性关节炎中，这是一种异常的调节。 射频合成和多样化是该病的基础 过程，而不仅仅是自身抗体的存在。建议数 实验意在确定异常调节的原因和 想出克服它的方法。这些实验的具体目的 主要有：(1)明确了三种不同的结构和遗传基础 人单克隆性RF重链上的CRIS；(2)独特型的鉴定 以及血液和滑膜中用于多克隆RF合成的基因 类风湿性关节炎患者；(3)明确生理功能 通过研究RF CRI前体B细胞在淋巴中的分布 器官，它们在对外源抗原的抗体反应中的利用， 以及它们在抗原-抗体复合体加工过程中的作用； 辨别HLADR抗原Dw4和Dr1是如何诱发异常的 暴露于环境抗原后持续的射频产生 (Epstein-Barr病毒gp110)复制类风湿性关节炎 DRβ-1链中的易感决定因素；以及(5)发展 可以预防或终止RF自身抗体产生的治疗方法 实验动物，最终用于类风湿性关节炎患者 以及其他与射频相关的疾病。