HLA-DRB1 ALLELE SPECIFIC SIGNALING ABERRATION IN RHEUMATOID ARTHRITIS

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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.