GENETICS AND BIOLOGY OF INTERLEUKIN 4 RECEPTOR IN JUVENILE RHEUMATOID ARTHRITIS

幼年类风湿性关节炎白细胞介素 4 受体的遗传学和生物学

• 批准号: 6100655
• 负责人: NEERU K HERSHEY
• 金额: $ 14.06万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6100655
• 关键词: atopy; cell line; cytokine receptors; family genetics; gel mobility shift assay; genetic polymorphism; genetic registry /resource /referral center; genetic susceptibility; genotype; helper T lymphocyte; human genetic material tag; interleukin 4; juvenile rheumatoid arthritis; pathologic process; site directed mutagenesis; transfection

Juvenile rheumatoid arthritis (JRA) is a prevalent pediatric condition and the most common cause of non-accidental acquired blindness in children. The etiology of JRA is unknown, but there is a genetic predisposition JRA is an inflammatory disease as evidenced by the presence of proinflammatory cytokines in the synovial fluid or synovium of affected joints. Two types of T helper subsets have been identified based on the profile of cytokines they produce. Th1 cells secrete predominately interferon-gamma (IFYgamma) and interleukin (IL)-2, while Th2 cells secrete predominately IL-4, IL-5, Il-13, and IL-10. IL-4 is a multifunctional cytokine secreted by Th2 cells and mast cells. IL-4 activates germline transcription of from the epsilon heavy chain locus and, together with signals delivered via the B cell surface molecule CD40, induces isotype switching from mu to epsilon. Studies both in vivo and in vitro have demonstrated that IL-4 is critical for the development of Th2 cells. This results in an amplification loop that perpetuates the Th2 response since IL-4 promotes Th2 development and ultimately the release of more IL-4. Recently, there have been several reports suggesting that JRA is predominantly a Th1-type disease. Since Th2 cytokines, and specifically IL-4, have been reported to have a protective effect in JRA, functionally relevant allelic variations in the IL-4Ralpha may have important roles in the genetics and pathogenesis of JRA. The longterm objective of these studies is to determine the functional consequences of the different IL-4Ralpha alleles and to delineate their role in the pathogenesis of JRA. These studies will provide novel insights into the pathogenesis and genetics of JRA. Furthermore, since the IL-4Ralpha and two of its alleles have been linked to atopic disease, it would be very interesting and novel to find the same alleles that predispose to one disease, i.e. atopy, may be protective in another disease, i.e. JRA. This would suggest an evolutionary balance between "disease susceptibility" and "disease protective" genes.

幼年类风湿性关节炎（JRA）是一种常见的儿科疾病 也是非意外获得性失明的最常见原因， 孩子JRA的病因尚不清楚，但有一种遗传 JRA是一种炎症性疾病， 滑液或滑膜中存在促炎细胞因子 受影响的关节。两种类型的辅助性T细胞亚群已被确定 基于它们产生的细胞因子的特征。Th 1细胞分泌 主要是干扰素-γ（IFN γ）和白细胞介素（IL）-2，而 Th 2细胞主要分泌IL-4、IL-5、IL-13和IL-10。 IL-4是 一种由Th 2细胞和肥大细胞分泌的多功能细胞因子。IL-4 激活来自重链基因座的胚系转录 并且与通过B细胞表面分子传递的信号一起 CD 40诱导同种型从mu转换为mu。体内研究 在体外实验中已经证明，IL-4对于 Th 2细胞。这导致了一个放大循环， Th 2应答，因为IL-4促进Th 2的发育，并最终导致Th 2的表达。 释放更多的IL-4。最近，有报道称 这表明JRA主要是一种Th 1型疾病。 由于Th 2细胞因子，特别是IL-4，已被报道具有 JRA中的保护作用， IL-4 R α可能在遗传学和发病机制中起重要作用 关于JRA这些研究的长期目标是确定 不同IL-4 R α等位基因的功能后果， 描述它们在JRA发病机制中的作用。这些研究将 为JRA的发病机制和遗传学提供了新的见解。 此外，由于IL-4 R α及其两个等位基因已被发现， 与特应性疾病有关，这将是非常有趣和新颖的发现， 易患一种疾病，即特应性的相同等位基因， 在另一种疾病中具有保护作用，即JRA。这表明 “疾病易感性”与“疾病”之间的进化平衡 保护性”基因。