GZMK-expressing CD8+ T cells promote recurrent airway inflammatory diseases

Nature, Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

Inflammatory diseases are often chronic and recurrent, current treatments do not typically remove underlying disease drivers1. T cells participate in a wide range of inflammatory such as psoriasis2, Crohn's disease3, oesophagitis4 multiple sclerosis5,6, clonally expanded antigen-specific may contribute to chronicity recurrence, part by forming persistent pathogenic memory. Chronic rhinosinusitis asthma airway that present comorbidities7. affects more than 10% the general population8. Among these patients, 20–25% would develop nasal polyps, which require repeated surgical resections owing high incidence recurrence9. Whereas abundant infiltrate polyps tissue10,11, cell subsets drive pathology promote recurrence fully understood. By comparing repertoires polyp tissues obtained from consecutive surgeries, here we report CD8+ clones carrying effector memory-like features colonize mucosal tissue during characteristically express tryptase Granzyme K (GZMK). We find GZMK cleaves many complement components, including C2, C3, C4 C5, collectively activation cascade. GZMK-expressing organized tertiary lymphoid structures, levels predict severity comorbidities better well-established biomarkers eosinophilia interleukin-5. Using mouse model, further show exacerbate manner dependent on proteolytic activity complements. Genetic ablation or pharmacological inhibition after onset markedly alleviates restores lung function. Our work identifies memory subset promotes inflammation recurrent molecule suggests potential therapeutic target. Comparing surgeries shows producing K, complement-activating tryptase, is

Язык: Английский

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C3‐dependent effector functions of complement

Immunological Reviews, Год журнала: 2022, Номер 313(1), С. 120 - 138

Опубликована: Окт. 22, 2022

Summary C3 is the central effector molecule of complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will introduce forms (native C3, [H 2 O], intracellular C3), fragments C3a, C3b, iC3b, C3dg/C3d, expression sites. To highlight important role that plays in human biological processes, we give an overview diseases linked to deficiency uncontrolled activation. Next, present a structural description activation generated by regulation. proceed describing C3a interaction with anaphylatoxin receptor, followed interactions opsonins (C3b, C3dg/C3d) receptors, divided into two groups: receptors bearing regulatory without activity. outline molecular architecture on fragments, cells expressing them, diversity functions, recent advances. With this review, aim up‐to‐date analysis processes triggered cell types health disease contexts.

Язык: Английский

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Screening of obstructive sleep apnea and diabetes mellitus -related biomarkers based on integrated bioinformatics analysis and machine learning

Sleep And Breathing, Год журнала: 2025, Номер 29(1)

Опубликована: Янв. 13, 2025

The pathophysiology of obstructive sleep apnea (OSA) and diabetes mellitus (DM) is still unknown, despite clinical reports linking the two conditions. After investigating potential roles for DM-related genes in OSA, our goal to investigate molecular significance condition. Machine learning a useful approach understanding complex gene expression data find biomarkers diagnosis OSA. Differentially expressed analysis OSA DM sets obtained from GEO were carried out firstly. Then four machine algorithms used screen candidate biomarkers. diagnostic model was constructed based on key genes, accuracy verified by ROC curve, calibration curve decision curve. Finally, CIBERSORT algorithm explore immune cell infiltration There 32 important that considered be related both datasets differentially analysis. Through enrichment analysis, majority these are enriched immunological regulation, oxidative stress response, nervous system control. When consensus characteristics all approaches predict diagnosis, STK17A thought have high degree accuracy. In addition, demonstrated strong performance predictive value. we explored cells signatures strongly linked invasive cells. has been discovered as can differentiate between individuals with methods. addition offering possible treatment targets DM-induced this identify high-risk patients who also

Язык: Английский

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Toward curing neurological autoimmune disorders: Biomarkers, immunological mechanisms, and therapeutic targets

Neuron, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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C3AR1 as a target for preeclampsia: from bioinformatics and network pharmacology to experimental validation

BMC Pregnancy and Childbirth, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 30, 2025

Preeclampsia, characterized by hypertension and proteinuria during pregnancy, poses significant risks to both mother fetus. The complement system's aberrant activation, notably the C3AR1, is important pathogenesis of preeclampsia, although precise mechanisms are not fully understood. Utilizing Comparative Toxicogenomics Database (CTD) Molecular Signatures (MSigDB), we identified system targets associated with preeclampsia environmental pollutants. Expression validation was conducted through Gene Omnibus (GEO) database. docking predicted interactions between BPA, PFOS, C3AR1. Immunohistochemical staining 80 placental tissues (40 early-onset 40 healthy controls) confirmed C3AR1 expression its clinical correlation. Integrated bioinformatics analyses revealed C3AR1's role in preeclampsia's molecular mechanisms. Functional verification assessed knocking down HTR-8/Svneo cells, including cell proliferation, invasion, apoptosis. Network pharmacology established connections pollutants as a key target. BPA PFOS binding Reduced preeclamptic placentas correlated maternal blood pressure, showed high diagnostic potential (AUC = 0.95). involvement linked Jak-STAT, TGF-β, HIF-1 pathways, NK M1 macrophage activity. knockdown cells decreased proliferation increased diminished tissues, correlating disease severity, suggesting biomarker. It crucial for cellular functions inflammation, future studies aiming leverage this novel treatments. Not applicable.

Язык: Английский

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Complement and the hallmarks of cancer

Seminars in Immunology, Год журнала: 2025, Номер 78, С. 101950 - 101950

Опубликована: Апрель 4, 2025

The hallmarks of cancer are a set traits that normal cells acquire during their transformation into malignancy. Among the biological processes influencing these hallmarks, innate immune complement system plays critical role. It can operate canonically-in blood and tissues-via phagocytosis, inflammation, complement-dependent cytotoxicity, similar to its roles against invading pathogens. Additionally, it functions non-canonically by modulating behavior within tumor microenvironment intracellular landscape which regulates cell fate. These mechanisms contribute complex context-dependent in both growth antitumor immunity, shaped characteristics dynamic microenvironment. This review analyses multifaceted interplay between proteins positioning this as target therapy.

Язык: Английский

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Geographic Atrophy in Age-Related Macular Degeneration

Ophthalmology Science, Год журнала: 2023, Номер 3(3), С. 100306 - 100306

Опубликована: Апрель 10, 2023

To examine disease progression in age-related macular degeneration (AMD) at 2 distinct stages, to geographic atrophy (GA) versus GA expansion, by comparison of the risk and protective factors each stage.Perspective.Individuals or with GA.Progression expansion rate.Critical synthesis literature on factors, both environmental genetic, for AMD.Comparison demonstrates partially overlapping but expansion. Some are shared (i.e., operating same direction stages), others not shared, seem operate different directions stage. Risk variants ARMS2/HTRA1 increase rate, presumably through mechanism. By contrast, CFH/CFHR alter rate. A variant C3 increases is associated slower In cigarette smoking increased faster whereas age former latter. The Mediterranean diet decreased although food components largest contributions differ between stages. phenotypic features, such as reticular pseudodrusen hyperreflective foci, stages.Analysis elements stage: some relevant 1 stage only, even active opposite Aside from ARMS2/HTRA1, overlap genetic stages minimal. This suggests that biologic mechanisms least has implications therapeutic approaches treatment aimed underlying processes may need be tailored stage.Proprietary commercial disclosure found after references.

Язык: Английский

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An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype

Cancer Immunology Research, Год журнала: 2024, Номер 12(3), С. 363 - 376

Опубликована: Янв. 30, 2024

Abstract Extensive infiltration by tumor-associated macrophages (TAM) in combination with myeloid-derived suppressor cells constitute the immunosuppressive microenvironment and promote malignant phenotype of gliomas. The aggressive mesenchymal (MES)-subtype glioma stem (GSC) are prominent However, underlying immune-suppressive mechanisms still unknown. current study showed that antitumor immune was activated Nfat1−/− mice, suggesting induction nuclear factor T cells-1 (NFAT1). In TAMs, NFAT1 could upregulate transcriptional activity complement 3 (C3) increase secretion C3a, which then bind to C3aR M2-like macrophage polarization activating TIM-3. Simultaneously, C3a/C3aR Ca2+-NFAT1 pathway, forming a positive feedback loop for further promoted MES transition GSCs. Finally, disruption this using inhibitor significantly inhibited growth both vitro vivo. demonstrated NFAT1-C3a-C3aR induces TAMs promotes GSCs, might be potential therapeutic target glioma.

Язык: Английский

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Local complement activation and modulation in mucosal immunity

Mucosal Immunology, Год журнала: 2024, Номер 17(4), С. 739 - 751

Опубликована: Июнь 4, 2024

Язык: Английский

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C1s targeting antibodies inhibit the growth of cutaneous squamous carcinoma cells

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июнь 12, 2024

Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The incidence of cSCC increasing globally and prognosis disease poor. Currently there are no specific targeted therapies for advanced or cSCC. We have previously shown abundant expression complement classical pathway C1 complex components, serine proteases C1r C1s in tumor cells invasive cSCCs vivo, whereas was lower situ, actinic keratoses normal skin. also that knockdown results decreased viability growth by promoting apoptosis both culture vivo. Here, we studied effect IgG2a mouse monoclonal antibodies TNT003 TNT005 targeting human five primary non-metastatic three lines show intracellular secretion into media. Treatment with significantly inhibited their promoted cells. These data indicate inhibit warrant further investigation inhibition additional vitro vivo models

Язык: Английский

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