Meeting Report: The Sixth International Sam Strober Workshop on Clinical Immune Tolerance

Transplantation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Language: Английский

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Deciphering Immunometabolic Landscape in Rheumatoid Arthritis: Integrative Multiomics, Explainable Machine Learning and Experimental Validation

Journal of Inflammation Research, Journal Year: 2025, Volume and Issue: Volume 18, P. 637 - 652

Published: Jan. 1, 2025

Immunometabolism is pivotal in rheumatoid arthritis (RA) pathogenesis, yet the intricacies of its pathological regulatory mechanisms remain poorly understood. This study explores complex immunometabolic landscape RA to identify potential therapeutic targets. We integrated genome-wide association (GWAS) data involving 1,400 plasma metabolites, 731 immune cell traits, and outcomes from over 58,000 participants. Mendelian randomization (MR) mediation analyses were applied evaluate causal relationships among cells, RA. further analyzed single-cell bulk transcriptomes investigate differential gene expression, interactions, relevant biological processes. Machine learning models identified hub genes, which validated via quantitative real-time PCR (qRT-PCR). Then, small-molecule drugs screened using Connectivity Map (CMAP) molecular docking. Finally, a phenome-wide (PheWAS) was conducted side effects targeting genes. Causalities found between six five cells genetically determined levels. Notably, DC mediated 18% protective effect PE on Autophagy-related scores elevated both subsets PE-associated Through observation functional differences cellular interactions clusters, DCs with high autophagy may process such as necroptosis activation Jak-STAT signaling pathway contributing pathogenesis Explainable machine learning, PPI network analysis, qPCR jointly four genes (PFN1, SRP14, S100A11, SAP18). CMAP, docking, PheWAS analysis highlighted vismodegib promising candidate. clarifies key RA, pinpointing paths for better prevention, diagnosis, treatment.

Language: Английский

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Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases

Annals of the Rheumatic Diseases, Journal Year: 2024, Volume and Issue: 83(10), P. 1233 - 1253

Published: May 3, 2024

Due to optimised treatment strategies and the availability of new therapies during last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art cannot induce remission. Moreover, risk for flares strongly increases once anti-inflammatory therapy is tapered withdrawn, suggesting that underlying pathological processes remain active absence overt inflammation. It has evident tissues ability remember past encounters with pathogens, wounds other irritants, react more and/or persistently next occurrence. This priming tissue bears a paramount role defence from microbes, but on hand drives pathologies (the Dr Jekyll Mr Hyde aspect adaptation). Emerging evidence suggests long-lived tissue-resident cells, fibroblasts, macrophages, plasma cells memory T determine an interplay infiltrating immune lymphoid myeloid origin, systemically acting factors cytokines, extracellular vesicles antibodies. Here, we review current state science priming, focusing tissue-occupying SSc, reflect most promising options targeting maladapted response these diseases.

Language: Английский

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The Differential Expressions and Associations of Intracellular and Extracellular GRP78/Bip with Disease Activity and Progression in Rheumatoid Arthritis

Bioengineering, Journal Year: 2025, Volume and Issue: 12(1), P. 58 - 58

Published: Jan. 13, 2025

GRP78/BiP, a stress-induced protein and autoantigen in rheumatoid arthritis (RA), exhibits different expressions various biological fluids tissues, including blood, synovial fluid (SF), synovium, all of which are pertinent to the disease activity progression RA; however, there is scarcity data linking both intracellular extracellular GRP78/Bip RA. This study was undertaken investigate differential expression SF, determine their association with Patients RA, osteoarthritis (OA), traumatic meniscal injury (TMI) without radiographic OA were consecutively recruited for study. Among patients six subgroups established based on progression. Disease measured using DAS28 (Disease scores 28 joints) criterion, while evaluated Steinbrocker classification grade. The levels GRP78/Bip, TNF-α, IL-10 significantly elevated serum, synovium RA when compared control (CON, TMI Patients) inflammation (iCON, groups (p < 0.05). In terms status, as opposed remission status serum However, found be reduced TNF-α remained elevated. With respect exhibited positive correlation stage synovium. Nonetheless, negative observed between correlations persisted. indicated that potential role function might vary depending its specific location within these tissues. presence associated suggesting involvement pathogenesis development this debilitating autoimmune disorder, well biomarker monitoring

Language: Английский

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CX3CR1+ age-associated CD4+ T cells contribute to synovial inflammation in late-onset rheumatoid arthritis

Inflammation and Regeneration, Journal Year: 2025, Volume and Issue: 45(1)

Published: Feb. 6, 2025

Abstract Background Recent evidence suggests that clonally expanded cytotoxic T cells play a role in various autoimmune diseases. Late-onset rheumatoid arthritis (LORA) exhibits unique characteristics compared to other RA forms, suggesting distinct immunological mechanisms. This study aimed examine the involvement of LORA. Methods Fresh peripheral blood samples were collected from 78 treatment-naïve active patients, 12 with difficult-to-treat RA, and 16 healthy controls. Flow cytometry was employed measure proportions CX3CR1 + CD4 CD8 these samples. Additionally, immunohistochemical staining performed on lymphoid node synovial biopsy patients RA. Results specifically increased untreated, LORA, displaying features CXCR3 mid age-associated helper known as “ThA”. CX3CR1⁺CD4⁺ identified ThA subset, nearly all expressed granzyme B. These observed enlarged lymph nodes found infiltrate tissues The positively correlated activity number decreased after treatment methotrexate, tumor necrosis factor inhibitors, interleukin-6 whereas T-cell activation modulators did not affect them. Moreover, PD-1 CD38 treatment-resistant cell subset characteristically showed no significant difference between individuals, correlation disease observed. However, age patients. Conclusions Our findings suggest immunopathogenesis differs by onset, playing presence specific may be linked resistance.

Language: Английский

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Promise of rheumatoid arthritis therapy: From clinical deep remission to drug-free

Best Practice & Research Clinical Rheumatology, Journal Year: 2025, Volume and Issue: unknown, P. 102031 - 102031

Published: Feb. 1, 2025

Language: Английский

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Unveiling the Crucial Role of CD8+ T Cell and Endothelial Cell Interaction in Rheumatoid Arthritis through the Integrated Analysis of Spatial Transcriptomics and Bulk/Single-Cell RNA-Seq

Journal of Translational Autoimmunity, Journal Year: 2025, Volume and Issue: 10, P. 100285 - 100285

Published: March 19, 2025

Language: Английский

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PD-L1+ Regulatory B Cells from Rheumatoid Arthritis Patients Have Impaired Function in Suppressing IFN-ү and IL-21 Production

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 2998 - 2998

Published: March 25, 2025

Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease. The pathomechanism of RA depends on both B and T cells. Regulatory cells (Breg) have been shown to suppress T-cell immune responses play key role in modulating processes. We aimed investigate the possibility utilizing PD-L1+ Breg downregulating Th cells' response healthy individuals patients. hypothesized that PD-1/PD-1L interaction plays this process, which may be defective diseases. separated from peripheral blood volunteers patients by magnetic cell sorting, Treg were isolated fluorescence-activated sorting. cytokine production CD4+ was detected intracellular flow cytometry. CpG CD40L stimulations applied induce PD-L1hi expressing found frequency significantly lower all B-cell subsets compared controls. Functional analysis induced coculture with activated autologous has control samples containing higher levels inhibit IFN-ү IL-21 In contrast, patients' failed do so. Since expression PD-L1 can modulated vitro suppressive capacity, these data provide new perspectives for future therapy RA.

Language: Английский

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Rheumatoid arthritis — the role of T cells in this complex systemic autoimmune disease

Current Opinion in Immunology, Journal Year: 2025, Volume and Issue: 94, P. 102555 - 102555

Published: April 9, 2025

Language: Английский

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Integration of transcriptome and immunophenotyping data highlights differences in the pathogenetic kinetics of B cells across immune-mediated disease

RMD Open, Journal Year: 2025, Volume and Issue: 11(2), P. e005310 - e005310

Published: April 1, 2025

Objective To elucidate crucial immune cell subsets and associated immunological pathways by stratifying patients with immune-mediated diseases (IMDs) using immunophenotyping transcriptomic approaches. Methods We conducted flow cytometric analyses in 23 derived from 235 six IMDs, our database, utilizing ImmuNexUT. Patients were stratified based on data. Subsequently, we examined clinical differences among these clusters. Results IMDs into two clusters their immunophenotypes. Cluster 1 was enriched differentiated B cells, including unswitched memory cells (USM B), switched double-negative plasmablasts, while cluster 2 naïve cells. Higher disease activity rheumatoid arthritis decreased respiratory functions systemic sclerosis observed 1, whereas the of lupus erythematosus higher 2. Numerous differentially expressed genes detected USM B. glycosylation processes elevated cell-activating factor signalling myeloid exhibited B-cell receptor 2, which had an age-associated signature, more frequent flares, suggesting that increased proportion this signature is poor prognosis. Conclusion Immunophenotyping-based transcriptome-based states revealed quantitative qualitative predict IMD prognosis, assessing both quantity quality may be crucial.

Language: Английский

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