Characterization of senescence biomarkers in rheumatoid arthritis: relevance to disease progression.

Rheumatoid arthritis (RA) has been associated with early senescent features. However, the effects of disease progression on senescence markers are largely unknown. Here, we evaluated key senescence markers in RA, including telomere length and T cell differentiation stages as well as cytomegalovirus (CMV) serology, previously associated with premature aging. In a cross-sectional study, 44 patients with active (Ac-RA), 26 patients with controlled (Co-RA), and 30 healthy controls were recruited. Peripheral blood was collected and differentiation stages of T cells analyzed by multi-color flow cytometry. Enzyme-linked immunosorbent assays were used to evaluate the CMV serology. The telomere length was measured by multiplex quantitative PCR. Patients with Ac-RA presented lower percentage of intermediate-differentiated T cells (CD4+CD27-CD28+ and CD8+CD27-CD28+; p < 0.001). All patients had a reduced proportion of cytotoxic T cells, and higher CD4/CD8 ratio compared with controls (p < 0.001). A lower proportion of CMV IgG+ subjects was found in the Co-RA group, (P < 0.001), although no differences in the CMV IgG titers were observed between groups. The groups had similar leukocyte telomere length. In addition, age was negatively correlated with CD8+CD27+CD28+ T (early-differentiated) cells (P < 0.05). Positive correlations between CMV IgG titers and age (P < 0.05) and CD4+CD27-CD28- T (late-differentiated) cells (P < 0.01) were observed. Furthermore, disease duration was correlated with CD4+CD27+CD28+ T cells (r = - 0.318, p < 0.05) and CD4+CD27-CD28- T cells (r = 0.308, p < 0.05). Our findings indicate that CMV and age may have a similar impact on T cells in both RA patients and controls. KEY POINTS: • Patients and controls were homogenous regarding CMV IgG titers and TL. • A lower proportion of CMV IgG+ subjects was found in the Co-RA group. • Anti-CMV levels were positively correlated with age and percentage of CD4+CD27-CD28- (late-differentiated) T cells.

Cognitive impairment in rheumatoid arthritis: role of lymphocyte subsets, cytokines and neurotrophic factors.

To what extent the cognitive impairment of rheumatoid arthritis (RA) is modulated by autoimmune and/or inflammatory activity is largely unknown. The aim of this study was to investigate the role of peripheral inflammation on cognitive functions of patients with active (Ac-), controlled (Co-) RA and healthy controls. In a cross-sectional study, 102 RA patients and 30 matched healthy controls were recruited. B and T cell subsets were immunophenotyped by flow cytometry. Plasma cytokines and neurotrophins were measured by flow cytometry and ELISA, respectively. Cognitive performance, depression and stress were evaluated by structured clinical interviews. Generalized linear modeling (GzLM) was used to compare differences between groups and multiple linear regression models were used to explore the predictive value of immune variables on cognitive performance. RA patients had overall cognitive impairment. Of note, the Ac-RA had the poorest performance on digit span (DST) and N-back when compared to Co-RA and control group (DST 9.9 ± 2.1, 12.9 ± 4.2, 15.5 ± 4.7, respectively; N-back 49.2 ± 8.3, 55.5 ± 11.1, 60.8 ± 9.1, respectively, all p < 0.0001). RA patients had expansions of immature B cells (Ac-RA 11.2 ± 7.1, Co-RA: 9 ± 5.7, control 5.9 ± 2.1) and plasma cells (Ac-RA 5.2 ± 2.5, Co-RA 6.9 ± 3.7, control 2.8 ± 1.7) as compared to controls, all p < 0.05. RA patients (controlled and active disease) had higher plasma levels of TNF, IL-2, IL-4, IL-6 and IL-10 than controls (all p < 0.002). RA patients had higher BDNF levels (Ac-RA 17,354.4 ± 5357.3, Co-RA 13,841.2 ± 5953.7, control 11,543.3 ± 3772), but lower GDNF levels [median (interquartile range) Ac-RA 0 pg/ml (0.0), Co-RA 0 pg/ml (4.6) and control 4.7 pg/ml (18.1)] than controls (all p < 0.05). RA patients had global cognitive impairment, which was associated with disease activity and immune changes.

Neuroendocrine and viral correlates of premature immunosenescence.

Aging continuously remodels the immune system, a process known as immunosenescence. Here, we review evidence of premature immunosenescence in younger individuals under conditions of chronic psychological stress, chronic inflammation, or exposure to certain persistent viral infections. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis and increased cortisol levels. Chronic stress is associated with thymic involution, blunted T cell proliferation, increased serum proinflammatory markers, and shorter telomere lengths. Human cytomegalovirus (CMV) infection has been implicated in accelerating immunosenescence by shrinking the T cell receptor repertoire and causing clonal expansion of senescent CD8(+) CD28(-) T cells with a proinflammatory profile. These factors increase inflammation associated with aging, or "inflammaging," particularly as it relates to etiology of several age-related diseases and increased mortality. Patients with rheumatoid arthritis have been shown to have several signatures of premature immunosenescence, including expansion of senescent T cells associated with cognitive impairment. We end by speculating that bipolar disorder can be considered as a model of accelerated aging because it has been associated with shortened telomeres, higher CMV IgG titers, and expansion of senescent and regulatory T cells.