No abstract

MTX decreases circulating purine and pyrimidine concentrations, and their availability for DNA and RNA synthesis, which may affect immune cell proliferation and protein (cytokine) expression. The absence of adenosine concentration changes and lack of ZTP formation is evidence against an AICAR/adenosine mechanism, although localized adenosine concentration changes cannot be excluded.

Human CD4+ T lymphocytes undergo aging-related changes leading to decreased immunity to infections and neoplasms, and to increased frequency of autoimmune diseases including rheumatoid arthritis (RA). Certain changes, observed in the CD4+ cells of RA patients, resemble those observed during physiological aging, but occur at earlier age. Underlying cellular mechanism(s) of these similarities are so far largely unknown. Here we show that KLOTHO, a β-glucuronidase gene whose activity changes are associated with aging phenotype, is down-regulated at the mRNA, protein, and enzymatic (β-glucuronidase) activity levels both in the healthy elderly and especially in RA CD4+ lymphocytes. Although the exact role of Klotho activity for CD4+ cell function is unknown, we propose here that it might be involved in anti-inflammatory processes occurring in the young and healthy individuals, but reduced in both healthy elderly and RA patients. To support this hypothesis, we show here that the reduction of Klotho expression and activity in both elderly and patients’ lymphocytes occurs in concert with the down-regulation of T cell costimulatory molecule CD28, the latter known to be dependent on increased levels of TNF-α. Thus, a common mechanism of KLOTHO down-regulation, but executed at various times in life, may underlie both physiological and disease-related T cell aging. Klotho activity might become a target of anti-RA drug development as well as a tool to help increase the immune system efficiency in the elderly.

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.

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.

Objectives Illness perception is a cognitive representation influencing physical and psychological functioning and adherence in patients with rheumatic disease. Studies exploring illness perception in systemic lupus erythematosus (SLE) are still scarce and none of them have investigated factors determining illness perception. We aimed to assess illness perception and to identify psychological, clinical and sociodemographic factors that might influence illness perception in SLE. Methods The study involved 80 patients with SLE (87.5% women, mean age 41.56 years). The Brief Illness Perception Questionnaire, State Trait Anxiety Inventory, Beck Depression Inventory, Pittsburgh Sleep Quality Index, Visual Analogue Scale-Pain and Fatigue Severity Scale were used. Clinical and sociodemographic data were collected via structured interview and medical files review. Results Illness perception was significantly positively correlated with anxiety, depression, sleep quality, fatigue and pain while it was not related to age, education, steroid treatment, disease duration and activity (SLEDAI) or organ damage (SLICC/ACR). Regression analysis revealed that state anxiety and depression explained 43% of illness perception variance. Cluster analysis identified three patient groups among which the middle-aged group had the most negative illness perception, the highest levels of anxiety, depression, pain and fatigue, and the poorest sleep quality. Conclusions The study has proved a significant relationship between negative illness perception and anxiety and depression. Patients reporting fatigue, poor sleep and pain might have special needs in terms of psychological intervention focused on negative illness perception and distress symptoms. Multidisciplinary care in managing SLE seems to be of great importance.

SummaryRheumatoid arthritis (RA) is a chronic inflammatory disease, with a clinical manifestation both systemic and in joints. It has been suggested that age at disease onset and/or patients' age have influence on disease activity and clinical outcome. The reasons for the different course of RA in older people are not known; however, the activation status of peripheral blood lymphocytes could be responsible. Our aim was to relate expression of activation markers in peripheral blood CD4 + T cells of RA patients with patients' age and/or onset age and disease activity measured by DAS28. Seventy RA patients were included into the immunological study. Two separation criteria were performed: based on age of RA onset and on the biological age of patients. We examined different activation markers, CD69, CD25, CD95 and human leucocyte antigen D-related (HLA-DR), on the CD4 + T cell surface. Division of RA patients in 10-year intervals at 40, 50 and 60 years revealed that RA patients with later disease onset were characterized by higher DAS28. This phenomenon was not limited to the division at 60 years of age but, surprisingly, the major differences were found for the 40-year onset division. Analysis of all four components of DAS28 revealed that disease activity in older disease onset was dependent on all components. Older-onset RA patients had a higher percentage of CD4 + CD25+ and CD4 + CD95 + T cells. Summarizing the major differences in DAS28 and activation status of CD4 + T cells observed for onset of disease at 40 years seems to be the most informative about the immunological status of RA patients.

This study aimed to evaluate changes in plasma amino acid and nicotinamide metabolites concentrations in rheumatoid arthritis (RA) in a search for potential biomarkers of the disease activity and the effect treatment. Analysis of plasma metabolite patterns with liquid chromatography/mass spectrometry revealed specific changes in RA as well as correlations with clinical parameters. Combined concentration parameter calculated as [aspartic acid] + [threonine] + [tryptophan] - [histidine] - [phenylalanine] offered the strongest correlation (p < 0.001) with pain joint count, swollen joint count and DAS 28. Such analysis of amino acid and related metabolite pattern offers potential for diagnosis as well as for monitoring disease progression and therapy in RA.