Objective To investigate the impact of rheumatoid arthritis (RA)-associated HLA-DRβ1*0401, *0402, *0403, *0404 and *0101 subtypes on the protein kinase A (PKA) signaling pathway. Methods Adenylate cyclase (AC), cAMP and PKA activity in transfectants expressing RA-associated HLA-DRβ1 subtypes and their mutants were detected. Results Compared to HLA-DRβ1*0402 transfectants, the RA-associated HLA-DRβ1*0401, *0404 and *0101 transfectants produced significantly lower levels of AC, cAMP and PKA. Conclusion RA-associated HLA-DRβ1 molecules are involved in the pathogenesis of RA through down-regulation of the PKA signaling pathway. Objective To investigate the impact of rheumatoid arthritis (RA) -associated HLA-DRβ1 * 0401, * 0402, * 0403, * 0404 and * 0101 subtypes on the protein kinase A (PKA) signaling pathway. Methods Adenylate cyclase and PKA activity in transfectants expressing RA-associated HLA-DRβ1 subtypes and their mutants were detected. Results Compared to HLA-DRβ1 * 0402 transfectants, the RA-associated HLA-DRβ1 * 0401, * 0404 and * 0101 transfectants produced significantly lower levels of AC, cAMP and PKA. Conclusion RA-associated HLA-DRβ1 molecules are involved in the pathogenesis of RA through down-regulation of the PKA signaling pathway.