HLA-DRB1 ALLELE SPECIFIC SIGNALING ABERRATION IN RHEUMATOID ARTHRITIS

类风湿性关节炎(RA)与特定的HLADRB1等位基因之间存在关联，这些等位基因的第三个等位基因高变区包含一个共同的表位。然而，这些MHC基因是如何赋予RA易感性的目前尚不清楚。目前领先的假说假设RA相关等位基因编码DRbeta链，这可能允许呈现假定的自身抗原。然而，这些致炎抗原的特性仍不清楚。这项拟议的研究提供了一种基于申请人实验室令人兴奋的初步数据的新范式。根据这一假设，共有的表位连续的β链干扰某些G蛋白偶联受体(GPCR)信号事件，使表达它们的细胞难以激活。这一假说是基于这样的观察，即转染了编码含有共同表位的DRB1等位基因的cDNA的HL A阴性细胞获得了与RA患者和自然表达这些DR基因的健康人的细胞相同的信号缺陷。此外，对点突变的cDNA转染体的分析表明，以前发现与RA易感性最相关的DRbeta链上的非常相同的残基是造成所观察到的异常的关键。初步结果表明，其机制可能涉及GPCR脱敏。这项研究的目的是对G蛋白受体激酶(GRKs)介导的GPCRs脱敏在异常中的作用进行全面的研究。

The association of rheumatoid arthritis (RA) with particular HLA DRB1 alleles containing a shared epitope in their third allelic hypervariable region is well documented. However, how those MHC genes confer RA susceptibility is presently unknown. The currently leading hypothesis postulates that RA-associated alleles encode DRbeta chains, which may allow presentation of putative self-antigens. The identity of such arthritogenic antigens, however, remains unknown. The proposed research is offering a novel paradigm based on exciting preliminary data in the applicant's laboratory. According to that hypothesis, shared epitope-contining beta chains interfere with certain G protein-coupled receptor (GPCR) signaling events in a way that renders cells expressing them refractory to activation. This hypothesis is based on the observation that HLA-negative cells transfected with cDNA encoding shared epitope-containing DRB1 alleles acquire the same signaling defects, which are found in cells of patients with RA and healthy individuals naturally expressing those DR genes. Furthermore, analysis of point-mutated cDNA transfectants demonstrates that the very same residues on the DRbeta chain, previously found to correlate best with RA susceptibility are essential for the observed aberration. Preliminary results suggest that the mechanism may involve GPCR desensitization. The goal of proposed research is to allow general examination of the role of G protein receptor kinases (GRKs) -mediated desensitization of GPCRs in the aberration.