Cytokines of the Th1 and Th2 type in sera of rheumatoid arthritis patients; correlations with anti-Hsp40 immune response and diagnostic markers.

Abstract

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease which affects approximately 1 % of the population worldwide. Recent research on the role of heat shock proteins (Hsps) in RA development indicates that they may have pro-or anti-inflammatory effect, most probably via modulating cytokine secretion. We investigated type Th1 (INFγ, TNFα, IL-2) and type Th2 (IL-10, IL-6, IL-4) cytokine levels in sera of RA patients and healthy controls, using flow cytometric bead array assay, and searched for correlations between the cytokine levels and serum antibodies against bacterial (DnaJ) and human (Hdj1, Hdj2 and Hdj3) Hsp40 proteins, as well as clinical and laboratory parameters. The levels of all cytokines studied were significantly increased in RA patients; the highest increase relative to healthy controls (7-fold) was observed for IL-6 and its levels correlated positively with the antibodies directed to DnaJ and to the C-terminal domain of Hdj2, and with diagnostic parameters (DAS 28, Steinbrocker RTG criteria, ARA/7, ESR, TEN, SW and GH). INFγ levels correlated negatively with DAS 28, ESR, TEN and SW. No correlations were found for TNFα, IL-2 or IL-4. Our results support the hypothesis of Hsp40 involvement in RA as well as indicate that IL-6 serum level is a good marker of the RA activity.

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 levels of the anti-DnaJ, anti-DNAJ1, and anti-DNAJ2 antibodies (IgG) in the sera of the RA patients ( n  = 43) and the control individuals ( n  = 35) were assayed by the ELISA test performed as described before (Tukaj et al 2010b). The antigens used were the Hsp40 proteins produced in the bacterial cells and, additionally, the DNAJA1 and DNAJA2 produced and farnesylated in the baculovirus system (designated as DNAJA1 f and DNAJA2 f ).…”

Patients with the most advanced rheumatoid arthritis remain with Th1 systemic defects after TNF inhibitors treatment despite clinical improvement

“…Previous assessments demonstrated no significant increment [13, 14, 31] or, alternatively, an increase in TNF-α or IL-17 in sera from RA patients [11, 12, 30, 32–35]. It seems reasonable that unstable in vitro activity of TNF-α and IL-17 probably resulting from the relatively short half-life of both cytokines might affect their detectable levels found in our experiments [35].…”

“…Previous assessments demonstrated no significant increment [13, 14, 31] or, alternatively, an increase in TNF-α or IL-17 in sera from RA patients [11, 12, 30, 32–35]. It seems reasonable that unstable in vitro activity of TNF-α and IL-17 probably resulting from the relatively short half-life of both cytokines might affect their detectable levels found in our experiments [35]. Since IL-6 has a much longer half-time and is closely and positively interrelated with TNF-α and IL-17 in all studied patients, it appears to reflect intrinsic concentrations of both factors, thus being a better disease marker for measurements in patients’ sera [35].…”

Association of self-reported symptoms with serum levels of vitamin D and multivariate cytokine profile in healthy women

“…With rheumatoid arthritis as an example, pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-17, are currently considered potential biomarkers 52,53. Further, levels of IL-6 and IL-17 have been reported to be associated with disease activity,53 GM-CSF to correlate with pain intensity,54 and levels of IL-6, IL-10, and IFN-γ to correlate with radiological progression 55. However, cytokines are known to work in a complex hierarchical network, and most of them show pleiotropic, redundant, and synergetic actions, making full understanding of the balance very challenging.…”