MOLECULAR MIMICRY AND RHEUMATOID ARTHRITIS

类风湿关节炎(RA)与人类白细胞抗原DR4的Dw4亚型有关。 这种联系的分子基础被认为是氨基酸。 在Dw4 b1链的第三高变区测序QKRAA。多么 这种共有的表位改变了类风湿关节炎的易感性，或者结果未知。我们的 初步实验表明：(1)QKRAA序列是 表达于两种人类病原体的主要抗原：Epstein-Barr 病毒(EBV)gp110蛋白和大肠杆菌dna J蛋白； 抗dna J蛋白的抗体与HLADw4β1链交叉反应； (Iii)与共享表位反应的T细胞存在于许多 不是HLADw4血型的正常成人；和(Iv)小鼠是 对与RA同源的自身MHC多肽的耐受性 表位。根据这些数据，我们推测QKRAA序列 在人类白细胞抗原中，DR4增加了对RA的易感性，因为它损害了免疫 调节大肠杆菌和EBV感染，和/或促进出现 可以触发自身免疫的交叉反应T细胞。建议数 实验将通过分析细微的特异性来验证这一假设 类风湿关节炎患者对dna J和gp110的免疫应答 表达或不表达QKRAA病易感性的正常受试者 表位。这些实验将利用野生型和突变型作为抗原 重组dna J和gp110蛋白以及相应的合成肽 分子的不同区域。有反应的细胞和血清将 来自同卵和异卵RA双胞胎，他们是一致的或 不和谐或不和谐的疾病，以及新近发病的患者 拉。在这些实验中收集的数据应该提供基本的 关于短小的人类白细胞抗原DR高变区多肽如何 改变对两种普遍存在的人类病原体的免疫反应，从而 影响类风湿关节炎的发病率或严重性。

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.