Hsp40 proteins modulate humoral and cellular immune response in rheumatoid arthritis patients

Abstract

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.

Human Hsp40 proteins, DNAJA1 and DNAJA2, as potential targets of the immune response triggered by bacterial DnaJ in rheumatoid arthritis

“…This hypothesis states that in RA, human Hsp40 protein(s) may be the targets of immune response induced by a bacterial DnaJ antigen (Albani et al 1995; Albani and Carson 1996). Our previous observations that sera derived from RA patients contain significantly elevated levels of anti-DnaJ, anti-DNAJA1, and anti-DNAJA2 (but not anti-DNAJB1) antibodies (Tukaj et al 2010a, b) are also consistent with the mimicry hypothesis. In this study, using a different set of the RA patient sera, we obtained similar results (Table S1, Supplementary data).…”

“…The presence of elevated levels of antibodies against the E. coli DnaJ has been shown in RA (Albani et al 1994, 1995; Chukwuocha et al 1999; Tukaj et al 2010a), with especially high response to the conserved J domain of DnaJ (Albani et al 1995; Tukaj et al 2010a). Additionally, an overexpression of human Hsp40s and significantly increased levels of the anti-DNAJA1 and anti-DNAJA2 antibodies have been found, respectively, in the synovial tissue and sera of RA patients (Kurzik-Dumke et al 1999; Tukaj et al 2010a).…”

“…The presence of elevated levels of antibodies against the E. coli DnaJ has been shown in RA (Albani et al 1994, 1995; Chukwuocha et al 1999; Tukaj et al 2010a), with especially high response to the conserved J domain of DnaJ (Albani et al 1995; Tukaj et al 2010a). Additionally, an overexpression of human Hsp40s and significantly increased levels of the anti-DNAJA1 and anti-DNAJA2 antibodies have been found, respectively, in the synovial tissue and sera of RA patients (Kurzik-Dumke et al 1999; Tukaj et al 2010a). Initially, a “molecular mimicry hypothesis” has been proposed, suggesting that the immune response directed against the bacterial DnaJ protein cross-reacts with the human homologous protein(s) and promotes development of RA; an infection with various bacterial species could trigger the response, since DnaJ is highly conserved among bacteria (Albani et al 1995; Albani and Carson 1996).…”

“…It has been demonstrated that T cells from patients with JIA respond differentially to peptides derived from bacterial and human Hsp40s and that regulatory T cells, induced by a peptide derived from a human Hsp40, downregulate proliferation of synovial fluid mononuclear cells of JIA patients (Massa et al 2007). Our previous study showed that DnaJ and human Hsp40 proteins inhibited proliferation of T cells of the RA patients and had an immunomodulatory effect on cytokine secretion by the patients’ lymphocytes (Tukaj et al 2010a). Although the exact role of bacterial and human Hsp40s in the autoimmune response requires further elucidation, it is clear that those proteins have a relevance in the clinical setting, especially since Hsp40s are considered as potential targets for anti-inflammatory therapy in JIA (Massa et al 2007) and RA (Tukaj et al 2010a).…”

“…Our previous study showed that DnaJ and human Hsp40 proteins inhibited proliferation of T cells of the RA patients and had an immunomodulatory effect on cytokine secretion by the patients’ lymphocytes (Tukaj et al 2010a). Although the exact role of bacterial and human Hsp40s in the autoimmune response requires further elucidation, it is clear that those proteins have a relevance in the clinical setting, especially since Hsp40s are considered as potential targets for anti-inflammatory therapy in JIA (Massa et al 2007) and RA (Tukaj et al 2010a). …”