Recent research on the heat shock proteins (Hsps) in chronic inflammatory diseases indicates that Hsps may have disease-suppressive activities. Our aim was to characterize immune response directed to bacterial (DnaJ) and human Hsp40s in patients with rheumatoid arthritis (RA). We found elevated levels of anti-DnaJ, anti-Hdj2, and anti-Hdj3 (but not ant-Hdj1) serum antibodies in the RA patients (P < or = 0.001) compared to healthy controls. In peripheral blood mononuclear cells (PBMCs) culture, all tested Hsp40 proteins significantly inhibited the divisions of CD4+ and CD8+ T cells of the RA patients but not those of the controls. Both DnaJ and Hdj2 stimulated secretion of the main anti-inflammatory cytokine IL-10 by PBMCs of the RA patients (P < 0.05), and of IL-6 by PBMCs of the RA (P < 0.001) and control (P < 0.01) groups. DnaJ reduced TNFalpha secretion (P < 0.05) by both groups of PBMCs. Our results show for the first time that the RA patients have an increased humoral response to human Hsp40 proteins Hdj2 and Hdj3. This is also the first description of immunomodulatory effect of human Hsp40s on T cells and cytokine secretion in RA, suggesting that Hsp40s act as natural anti-inflammatory agents in RA.