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.
Rheumatoid arthritis (RA) and osteoarthritis (OA) are chronic diseases associated with morphological joint changes. Synovial membrane (SM) involvement was established for RA, but the data for OA are limited, because OA is usually regarded as noninflammatory disease. Changes in immune system in RA are not limited to joints, and the significant role of T cells of peripheral blood (PB) is not disputable. However, there is still an open debate about PB immunological profile in OA. Therefore, we decided to measure the distribution of CD4 + and CD8 + T cells, regarding CD28 expression, both in PB and SM of RA and OA patients, on the same day. Altogether, eleven RA patients, 11 OA patients and similar numbers of age-matched healthy controls were included into the study. Flow cytometry was used for T cells subpopulation distinguishing and quantification; monoclonal antibodies against CD3, CD4, CD8 and CD28 with different fluorochromes were used for stainings. The RA patients had significantly higher percentage of CD3 + 4 + cells in PB as compared to OA patients and relevant control group. Both within the CD4 + and CD8 + compartments, significantly lower percentages of cells bearing the CD28 marker were found in the PB of OA as compared to RA patients. The proportion of CD3 + CD4 + cells in SM was dependent on age of OA patients, older OA patients had significantly higher value of their SM/blood ratio than RA patients. Older OA subjects were also characterized by higher values of the SM/blood ratio of both CD4 + CD28 + and CD8 + CD28 + subpopulations than RA or younger OA patients. In conclusion, in contrast to the traditional view of OA disease, our results give support to the hypothesis that OA may also (like RA) be a disease with a local immunological involvement.
Summary The CD28 gene is similarly down‐regulated in CD4+ lymphocytes from both healthy elderly people and patients with rheumatoid arthritis (RA) because of impaired protein‐binding activity of the ‘α’ sequence in its promoter region. Other genes important for the CD4+ cell function may share that sequence and may be similarly regulated and affected. We searched GenBank for possible ‘α’ homologues and then compared transcriptional activities of the respective genes in the CD4+ cells of young and older healthy individuals and those with RA by real‐time PCR. We show here that genes encoding one of the zinc finger proteins (ZNF334), the ‘aging hormone’ Klotho, the retinoid acid receptor β2 (RARβ2) and the T‐cell adapter protein GRAP‐2, contain sequences with various (exceeding 70%) degrees of homology to the ‘α’ sequence near their promoters. These genes are transcribed in human CD4+ lymphocytes; the expressions of RARβ2, KLOTHO and ZNF334 are significantly decreased in a correlated manner in the cells of patients with RA compared with those of healthy individuals. In RA patients, the extremely reduced expression of ZNF334 does not depend on the individual’s age, apparently constituting a disease‐related phenomenon; whereas that of RARβ2 and KLOTHO occurs mostly in the cells of relatively younger patients, making them similar to the lymphocytes of healthy elderly in this aspect.
It has been hypothesized that α-Klotho deficiency might contribute to chronic inflammation in patients with end-stage renal disease (ESRD), especially those on hemodialysis (HD). Serum Klotho levels by some authors are considered a potential predictor of cerebrovascular events. Therefore, we analyzed serum levels of α-Klotho with ELISA and inflammation-related cytokines in HD patients. Sixty-seven HD patients and 19 healthy people were recruited between November 2017 and June 2021. A Cytometric Bead Array (CBA) was used to determine the level of different cytokines: IL-12p70, TNF, IL-10, IL-6, IL-1β, and IL-8. A human Klotho ELISA kit was used to determine the level of α-Klotho in the plasma samples of HD patients. There was no difference in serum levels of α-Klotho between HD patients and healthy people. Patients had increased serum IL-6 and IL-8. Significant positive correlations existed between the concentration of α-Klotho and the serum concentrations of IL-12p70, IL-10, and IL-1β. However, in a multivariable linear regression analysis, only patients’ age was associated independently with α-Klotho level. Serum α-Klotho was not associated with higher mortality risk in HD patients. While these results draw attention to potential relationships between α-Klotho proteins and inflammatory markers in HD patients, our cross-sectional study could not confirm the pathogenic link between α-Klotho, inflammation, and cardiovascular mortality.
INTROduCTION Rheumatoid arthritis (RA) is a chronic autoimmune disease and it is known that lymphocytes play a major role in its pathogenesis. However, there have been no comprehensive studies on the changes in peripheral blood lymphocyte (PBL) subpopulations expressing different clusters of differentiation (CD) in patients with long-lasting RA. ObjECTIvEs The aim of our study was to measure the main subpopulations of PBL, expression of costimulatory marker CD28, and activation status of CD4 + T cells depending on clinical disease activity in long-lasting RA. PATIENTs ANd mEThOds The study comprised 60 patients with RA and 19 healthy volunteers. Disease activity, the proportion and number of the main PBL subpopulations (T, B, natural killer [NK], and NK T cells [NKT]), the expression of costimulatory marker CD28, and the activation status of CD4 + T cells were evaluated on the same day. A multicolor flow cytometry with marked monoclonal antibodies was used for the assessment of lymphocyte subpopulations. REsuLTs The percentage of CD3 + CD4 + , NKT, CD4 + CD28-, CD8 + CD28-, CD4 + CD69 + , CD4 + CD25 + , and CD4 + HLA-DR + was significantly higher in RA compared with the control group. A higher proportion of CD4 + CD28was associated with more active disease, while an inverse correlation was observed for B cells. The proportion of CD4 + CD28was not associated with disease activity. The number of CD4+CD69+ cells in RA patients increased with increasing DAS28, while the number of CD4 + HLA-DR + T cells showed no such association. CONCLusION Our results have shown for the first time an association between the phenotype patterns of PBL T, B, and NKT and RA activity in patients with long-lasting disease, which reinforces the hypothesis that PBL play an important role in modifying or maintaining the disease activity.
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