HLA-DRB1 ALLELE SPECIFIC SIGNALING ABERRATION IN RHEUMATOID ARTHRITIS

类风湿性关节炎（RA）与在其第三等位基因高变区中含有共享表位的特定HLA-DRB 1等位基因的关联被充分记录。然而，这些MHC基因如何赋予RA易感性目前尚不清楚。目前主要的假说假定RA相关等位基因编码DR β链，这可能允许呈现推定的自身抗原。然而，这种致关节炎抗原的身份仍然未知。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，共享的表位-持续β链干扰某些G蛋白偶联受体（GPCR）信号传导事件，使表达它们的细胞难以活化。这一假设是基于这样的观察，即用编码含有共享表位的DRB 1等位基因的cDNA转染的HLA阴性细胞获得相同的信号传导缺陷，这在RA患者和天然表达这些DR基因的健康个体的细胞中发现。此外，点突变的cDNA转染子的分析表明，DR β链上的非常相同的残基，以前发现最好的相关性与RA的易感性是必不可少的观察到的畸变。初步结果表明，其机制可能涉及GPCR脱敏。拟议的研究的目标是允许一般检查的作用G蛋白受体激酶（GRKs）介导的脱敏的GPCR的畸变。

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.