Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(38)

Published: Sept. 11, 2024

Chaperone-mediated autophagy (CMA) is a selective form of that contributes to the maintenance cellular homeostasis. CMA activity declines with age in most tissues and systems, including immune system, due reduction levels lysosome-associated membrane protein type 2A (LAMP2A), an essential component. In this study, we show overexpressing copy hLAMP2A within T cells since middle-age can prevent some their age-associated loss function. Our data support idea preserving LAMP2A expression through genetic means leads enhanced proliferative responses, decreased number regulatory cell populations, down-regulated inhibitory receptors by cells. During aging, elevated numbers these immunosuppressive populations significantly contribute downregulation responses. Using comparative proteomics, confirm preservation old mice prevents age-related changes both resting activated proteome. We also explore effect using first-in-class small molecule activators demonstrate improved response upon administration mice. conclude sustaining constitutes potentially viable therapeutic approach improving function age.

Language: Английский

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Molecular mimicry in the pathogenesis of autoimmune rheumatic diseases

Journal of Translational Autoimmunity, Journal Year: 2025, Volume and Issue: 10, P. 100269 - 100269

Published: Jan. 8, 2025

Autoimmune rheumatic diseases (ARDs) are a heterogeneous group of conditions characterized by excessive and misdirected immune responses against the body's own musculoskeletal tissues. Their exact aetiology remains unclear, with genetic, demographic, behavioural environmental factors implicated in disease onset. One prominent hypothesis for initial breach tolerance (leading to autoimmunity) is molecular mimicry, which describes structural or sequence similarities between human microbial proteins (mimotopes). This similarity can lead cross-reactive antibodies T-cell receptors, resulting an response autoantigens. Both commensal microbes microbiome pathogens trigger thereby potentially contributing onset ARDs. In this review, we focus on role mimicry rheumatoid arthritis systemic lupus erythematosus. Moreover, implications also briefly discussed ankylosing spondylitis, sclerosis myositis.

Language: Английский

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Decreased serum TIMP4 levels in patients with rheumatoid arthritis

Open Life Sciences, Journal Year: 2025, Volume and Issue: 20(1)

Published: Jan. 1, 2025

Abstract The current study was designed to explore the clinical significance of serum tissue inhibitor metalloproteinase 4 (TIMP4) levels in rheumatoid arthritis (RA). GSE1919 chip analyzed, differentially expressed genes (DEGs) were identified, and gene ontology as well Kyoto Encyclopedia Genes Genomes analyses identified DEGs conducted. Patients with RA ( n = 96) healthy individuals enrolled this study. Serum from participants collected, RT-qPCR WB have been conducted examine TIMP4 levels; additionally, interleukin (IL)-6 IL-1β determined using ELISA method. Pearson’s correlation analysis for evaluating relationships between expression those IL-6 or IL-1β. A receiver operating characteristic (ROC) curve drawn determine potential diagnostic value RA. a markedly downregulated involved development. significantly decreased patients RA, results ROC showed that may be marker. Furthermore, concentrations elevated Finally, negative either is reliable marker diagnosis.

Language: Английский

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Insights into targeting cellular senescence with senolytic therapy: The journey from preclinical trials to clinical practice

Mechanisms of Ageing and Development, Journal Year: 2024, Volume and Issue: 218, P. 111918 - 111918

Published: Feb. 23, 2024

Language: Английский

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The inter-link of ageing, cancer and immunity: findings from real-world retrospective study

Immunity & Ageing, Journal Year: 2023, Volume and Issue: 20(1)

Published: Dec. 15, 2023

Although the concept of declined immune function associated with cancer has been accepted extensively, real-world clinical studies focusing on analysis peripheral blood changes underlying ageing, immunity and are scarce.In this case-control study, we retrospectively analysed 1375 patients enrolled 275 age gender matched healthy individuals. Flow cytometry was conducted to assess changes. Further examined by SPSS 17.0 GraphPad Prism 9 software.Cancer showed obviously decreased CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B, CD16+CD56+ NK cell counts lower percentage PD-1 (programmed death protein-1, PD-1) positive cells than control (P < 0.0001). For patients, reference range circulating PD-1+CD45+ cells, PD-1+CD3+ T PD-1+CD3+CD4+ Th PD-1+CD3+CD8+ CTL (Cytotoxic Lymphocyte, CTL) were 11.2% (95% CI 10.8%-11.6%), 15.5% 14.7%-16.0%), 15.4% 14.9%-16.0%) 14.5% 14.0%-15.5%), respectively. Moreover, reduction B accompanied stage advancing 0.05). stage, but elevated in aged male Additionally, varied across types, raised stage. Head neck, pancreatic, gynaecological lung demonstrated a higher level melanoma, prostate, breast 0.05).This study provides blood, confirms series accompanying cancer, expands our real world evidence better understand interactions immunity. shows similar tumor type distribution mutational burden (TMB), supports that it maybe potential predictive biomarker for checkpoint inhibitor therapy.

Language: Английский

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An in-depth understanding of the role and mechanisms of T cells in immune organ aging and age-related diseases

Science China Life Sciences, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 2, 2024

Language: Английский

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The role of autoantibodies in bridging obesity, aging, and immunosenescence

Immunity & Ageing, Journal Year: 2024, Volume and Issue: 21(1)

Published: Nov. 30, 2024

Abstract Antibodies are essential to immune homeostasis due their roles in neutralizing pathogenic agents. However, failures central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance generate autoantibodies mistakenly target self-antigens, leading inflammation autoimmune diseases. While well-studied some communicable diseases, chronic conditions, such as obesity aging, less understood. Obesity aging share similar aspects of dysfunction, diminished humoral responses heightened inflammation, which disrupt tolerance foster autoantigen production, thus giving rise autoantibodies. In return, these events may also contribute the pathophysiology associated disorders linked development immunosenescence, an age-related decline function heightens vulnerability infections, loss self-tolerance. Furthermore, cumulative exposure antigens cellular debris during perpetuates pro-inflammatory pathways, linking immunosenescence with other hallmarks, proteostasis mitochondrial dysfunction. This review examines mechanisms driving autoantibody generation discusses key putative antigenic targets across conditions. We explore therapeutic potential emerging approaches, CAR-T/CAAR-T therapies, vaccines, BiTEs, tackle autoimmune-related conditions obesity.

Language: Английский

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Immune checkpoints in autoimmune vasculitis

Best Practice & Research Clinical Rheumatology, Journal Year: 2024, Volume and Issue: 38(2), P. 101943 - 101943

Published: May 1, 2024

Language: Английский

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Fluid biomarkers unveil signatures of pathological aging

Seizure, Journal Year: 2024, Volume and Issue: unknown

Published: May 1, 2024

Aging is a multifaceted and highly varied process in the brain. Identifying aging biomarkers one means of distinguishing pathological from physiological aging. The aim this narrative review to focus on two new developments field fluid draw attention excellent tool for early detection potential brain pathologies that delay, alter, or enable become pathological. Pathological can lower threshold development specific diseases such as late-onset epilepsy. Fluid reveal levels at an stage thus indicate disease processes begin before symptoms develop; they differ

Language: Английский

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Effect of the immune cells and plasma metabolites on rheumatoid arthritis: a mediated mendelian randomization study

Frontiers in Endocrinology, Journal Year: 2024, Volume and Issue: 15

Published: Sept. 3, 2024

Background Increasing evidence indicates a close relationship between alterations in human immune cells and plasma metabolites with Rheumatoid Arthritis (RA). However, limited studies have left the causal relationships behind these links unclear. Methods A bidirectional Mendelian Randomization (MR) study was conducted, combined mediation analysis, using data from genome-wide association database covering 731 cell phenotypes 1,400 metabolite traits to explore their RA potential mediating effects. The primary method used for MR analysis inverse-variance weighted False Discovery Rate (FDR) correction applied verify robustness of our results. Results HLA DR on CD33- DR+ (myeloid group) (OR, 1.422; 95% CI, 1.194–1.694; P &lt; 0.001; FDR = 0.012) increased risk developing RA. CD19 IgD+ CD38- naive (B 0.969; 0.954–0.985; 0.021) reduced factor CD14- CD16+ monocytes (monocyte 1.242; 1.102–1.401; 0.047). protective memory B %lymphocyte 0.861; 0.795–0.933; 0.050), CD4+ CD8dim T (TBNK 0.802; 0.711–0.904; 0.043), %leukocyte 0.814; 0.726–0.913; 0.046), CD24 CD24+ 0.857; 0.793–0.927; 0.038), unswitched 0.867; 0.797–0.942; 0.050). levels docosatrienoate (22:3n3) 0.886; 0.838–0.936; 0.023) significantly effect this context not established. Conclusion This provides genetic intricate cells, metabolites, RA, highlighting mechanisms involved. will contribute future directions precision medicine research.

Language: Английский

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