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Cellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age‐associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence‐associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging. [ABSTRACT FROM AUTHOR]

The conserved serine residues S866 and S870 are the major phosphorylation sites essential for the processing of p100 to p52 in cells. Keywords: Common Variable Immunodeficiency (CVID); NFKB2; novel pathogenic gene variants; lym1 mice; hypogammaglobulinaemia; autoimmunity EN Common Variable Immunodeficiency (CVID) NFKB2 novel pathogenic gene variants lym1 mice hypogammaglobulinaemia autoimmunity 1159 1164 6 07/20/23 20230801 NES 230801 Kruthika Sundaram and Micol Ferro contributed equally to this work. The reduction of p100 processing was linked to a markedly less increased phosphorylation of p100 in Patient 1 compared to the controls - which is likely caused by the absence of S870 in the p100 truncated form (p.Tyr868*). The two major phospho-serines (S866 & S870) create a binding site for -TrCP, the receptor subunit of the E3 ubiquitin ligase -TrCP SP SCF sp , which mediates p100 ubiquitination and its proteasomal-dependent processing to p52 employing the p100 ubiquitin acceptor site lysine 855 [[3]]. [Extracted from the article]

CD8(+) T cells specific to caspase-cleaved antigens derived from apoptotic T cells represent a principal player in chronic immune activation. Here, we found that both apoptotic epitope-specific and hepatitis C virus (HCV)-specific CD8(+) T cells were mostly confined within the effector memory (EM) or terminally differentiated EM CD45RA(+) cell subsets expressing a dysfunctional T-helper 1-like signature program in chronic HCV infection. However, apoptotic epitope-specific CD8(+) T cells produced tumor necrosis factor α and interleukin 2 at the intrahepatic level significantly more than HCV-specific CD8(+) T cells, despite both populations expressing high levels of programmed death 1 receptor. Contextually, only apoptotic epitope-specific CD8(+) T cells correlated with both interferon-stimulated gene levels in T cells and hepatic fibrosis score. Together, these data suggest that, compared with HCV-specific CD8(+) T cells, apoptotic epitope-specific CD8(+) T cells can better sustain chronic immune activation, owing to their capacity to produce tumor necrosis factor α, and exhibit greater resistance to inhibitory signals during chronic HCV infection. [ABSTRACT FROM AUTHOR]

CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients. [ABSTRACT FROM AUTHOR]

A variety of physiological and pathological conditions may induce cell death. Therefore, it is reasonable that apoptotic cells send different signals promoting either tolerance or immune responses. Many factors influence the type of response, such as the quality (e.g. bearing or released factors, activation state), the timing and the site of cell death. In particular, the activation state of apoptotic lymphocytes (CD40L expression) may be crucial in determining the fate of their cross-presentation, i.e. cross-tolerance versus cross-priming. The cross-presentation of apoptotic activated CD40L+ T cells determines the cross-priming of apoptotic epitope-specific CD8+ T cells. These autoreactive CD8+ T cells are observed in diseases with a sustained component of chronic inflammation such as chronic viral infections and systemic autoimmune diseases. We have explored this phenomenon in HIV and chronic hepatitis C virus infections as well as in multiple sclerosis and rheumatoid arthritis, all conditions where these CD8+ T cells participate in the maintenance of a low-level state of inflammation. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Here, we evaluated the hypothesis that CD8+ T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology. Methods: The percentage of autoreactive CD8+ T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer+ CD8+ T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo. Results: We found that polyfunctional (IFN-? and/or IL-17 producing) autoreactive CD8+ T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8+ T cells with a strong potential to produce IFN-? or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8+ T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8+ T cells ex vivo. Conclusion: Taken together, these data indicate that apoptotic epitope-specific CD8+ T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Purpose: To quantify the health related quality of life in primary immunodeficiency patients. Materials and Methods: We used generic health status and general psychological health questionnaires to determine the range of issues that needed to be considered in examining the burden of common variable immunodeficiency (CVID). Results: The health status of patients with CVID was lower than that observed in normal subjects. Overall, Role-Physical and General Health scales correlated with a poorer clinical status. Surprisingly, the duration of disease did not influence health status. Being female, older, General Health Questionnaire-positive and alexithymic proved to be major risk factors associated with a poor health status. Patients with chronic lung disease and chronic diarrhea had the lowest values on the Medical Outcome Study, Short Form SF-36 (SF-36) scales. Disease severity perception was associated with the General Health Questionnaire and alexithymia status. Limitations in daily activities as a result of lower physical health were the major problems facing common variable immunodeficiency patients. Conclusion: Our data underlined the importance of conducting a periodical health related quality of life assessment on patients with primary antibody deficiencies and, moreover, stressed the necessity of providing psychological support to at risk patients. [ABSTRACT FROM AUTHOR]

Background: Here, we evaluated the hypothesis that CD8+ T cell responses to caspase-cleaved antigens derived from effector T cells undergoing apoptosis, may contribute to multiple sclerosis (MS) immunopathology.Methods: The percentage of autoreactive CD8+ T effector cells specific for various apoptotic T cell-associated self-epitopes (apoptotic epitopes) were detected in the peripheral blood and cerebrospinal fluid (CSF) by both enzyme-linked immunospot and dextramers of class I molecules complexed with relevant apoptotic epitopes. Moreover, the capacity of dextramer+ CD8+ T cells to produce interferon (IFN)-γ and/or interleukin (IL)-17 in response to the relevant apoptotic epitopes was evaluated by the intracellular cytokine staining. Cross-presentation assay of apoptotic T cells by dendritic cells was also evaluated ex vivo.Results: We found that polyfunctional (IFN-γ and/or IL-17 producing) autoreactive CD8+ T cells specific for apoptotic epitopes were represented in MS patients with frequencies significantly higher than in healthy donors. These autoreactive CD8+ T cells with a strong potential to produce IFN-γ or IL-17 in response to the relevant apoptotic epitopes were significantly accumulated in the CSF from the same patients. In addition, the frequencies of these autoreactive CD8+ T cells correlated with the disease disability. Cross-presentation assay revealed that caspase-cleaved cellular proteins are required to activate apoptotic epitope-specific CD8+ T cells ex vivo.Conclusion: Taken together, these data indicate that apoptotic epitope-specific CD8+ T cells with strong inflammatory potential are recruited at the level of the inflammatory site, where they may be involved in MS immunopathology through the production of high levels of inflammatory cytokines. [ABSTRACT FROM AUTHOR]