MOLECULAR MIMICRY AND RHEUMATOID ARTHRITIS

分子拟态与类风湿性关节炎

• 批准号: 3728168
• 负责人: DENNIS A CARSON
• 金额: --
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3728168
• 关键词: T cell receptor; T lymphocyte; antibody specificity; antigen antibody reaction; autoimmunity; bacterial proteins; blood chemistry; cellular immunity; disease /disorder proneness /risk; dizygotic twins; enzyme linked immunosorbent assay; epitope mapping; gene expression; genotype; glycoproteins; histocompatibility antigens; human subject; humoral immunity; immune response genes; in situ hybridization; molecular pathology; monozygotic twins; pathologic process; polymerase chain reaction; rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with the Dw4 subtype of HLA DR4. The molecular basis for this association is thought to be the amino acid sequence QKRAA in the third hypervariable region of the Dw4 b1 chain. How this shared epitope alters RA susceptibility or outcome is not known. Our preliminary experiments have shown (i) that the QKRAA sequence is expressed on major antigens from two human pathogens, the Epstein-Barr virus (EBV) gp110 protein and the E.coli dnaJ protein; (ii) that antibodies against the dnaJ protein cross-react with HLA Dw4 beta1 chains; (iii) that T cells reactive with the shared epitope are present in many normal adult humans that do not type as HLA Dw4; and (iv) that mice are tolerant to self MHC peptides that are homologous to the RA shared epitope. Based upon the data, we have postulated that the QKRAA sequence in HLA DR4 increases susceptibility to RA because it impairs immune regulation of E.coli and EBV infections, and/or promotes the emergence of cross-reactive T cells that can trigger autoimmunity. The proposed experiments will test this hypothesis by analyzing the fine specificity and magnitude of immune responses to dnaJ and gp110 in RA patients and normal subjects who do or do not express the QKRAA disease susceptibility epitope. The experiments will utilize as antigens wild type and mutant recombinant dnaJ and gp110 proteins, and synthetic peptides corresponding to different regions of the molecules. The responding cells and sera will come from both monozygotic and dizygotic RA twins, who are concordant or discordant or discordant for disease, and from patients with recent onset RA. The data collected in these experiments should provide fundamental information concerning how a short HLA DR hypervariable region peptide can change immune responses to two ubiquitous human pathogens, and thereby affect RA incidence or severity.

风湿性关节炎（RA）与HLA DR 4的Dw 4亚型有关。 这种结合的分子基础被认为是氨基酸 在Dw 4 b1链的第三高变区中的序列QKRAA。 如何 该共有表位改变RA易感性或结果尚不清楚。 我们 初步实验表明（i）QKRAA序列是 表达于来自两种人类病原体的主要抗原上， 病毒（EBV）gp 110蛋白和大肠杆菌dnaJ蛋白;（ii） 抗dnaJ蛋白的抗体与HLA Dw 4 β 1链交叉反应; (iii)与共享表位反应的T细胞存在于许多 不分型为HLA Dw 4的正常成年人;和（iv）小鼠是 耐受与RA共享的同源的自身MHC肽 表位 基于这些数据，我们假设QKRAA序列 在HLADR 4中，由于它损害免疫系统， 调节大肠杆菌和EBV感染，和/或促进 交叉反应性T细胞可以引发自身免疫。 拟议 实验将通过分析精细的特异性来检验这一假设。 RA患者对dnaJ和gp 110的免疫应答的大小， 表达或不表达QKRAA疾病易感性的正常受试者 表位 实验将利用野生型和突变型作为抗原 重组dnaJ和gp 110蛋白以及相应的合成肽 分子的不同区域。 应答细胞和血清将 来自同卵和异卵RA双胞胎，他们是一致的， 与疾病不一致或不一致，以及来自近期发作的患者 RA. 在这些实验中收集的数据应该提供基本的 关于短HLADR高变区肽如何 改变对两种普遍存在的人类病原体的免疫反应， 影响RA发病率或严重程度。