Immunology最新文献

Beyond their classical role as cellular powerhouses, mitochondria are now recognised as indispensable hubs for innate immune signalling. A pivotal aspect of this function is the release of mitochondrial DNA (mtDNA), a potent damage-associated molecular pattern (DAMP) that, when misplaced, acts as a powerful alarmin due to its prokaryotic origins. In response to cellular stress or infection, mtDNA translocates to the cytosol and activates intracellular protein platforms known as inflammasomes, triggering the maturation of cytokines like interleukin-1β (IL-1β) and inducing a lytic form of cell death, pyroptosis. This review synthesises current research on this intricate relationship. Whilst potassium (K⁺) efflux remains the canonical trigger for the NLR family pyrin domain containing 3 (NLRP3) inflammasome, emerging and debated roles of oxidised mtDNA (ox-mtDNA) as a potential direct ligand or critical upstream amplifier are explored. The manuscript elucidates mtDNA release mechanisms, such as mitochondrial permeability transition pore (mPTP) opening, and explores the role of amplifying pathways like the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) axis and cytidine/uridine monophosphate kinase 2 (CMPK2)-mediated mtDNA synthesis. The profound involvement of the mtDNA-inflammasome axis is surveyed across a spectrum of pathologies, including autoimmune, metabolic, neurodegenerative, and cardiovascular diseases. The compiled evidence establishes mtDNA as a universal trigger of inflammation and a unifying pathogenic driver across this diverse disease landscape, highlighting the significant therapeutic potential of modulating this fundamental immune signalling axis to treat a multitude of human diseases.

Long COVID affects a substantial proportion of survivors of acute infection with severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2), who suffer a variety of symptoms that limit their quality of life and economic activity. Although the aetiology of long COVID is obscure, it appears to be a chronic inflammatory condition. Complement dysregulation is a prevalent feature of long COVID. Specifically, markers of classical, alternative, and terminal pathway activation are often elevated in patients with this condition. Here, we used a sensitive assay for mannan-binding lectin-associated serine protease-2 (MASP-2)/C1Inh complexes to analyse lectin pathway activation in a previously characterised cohort of patients with long COVID (n = 159) and healthy convalescent individuals with no persistent symptoms after infection with SARS-CoV-2 (n = 76). The data were combined with those from the most predictive complement analytes identified previously to delineate potential biomarkers of long COVID. MASP-2/C1Inh complexes were significantly elevated in patients with long COVID (p = 0.0003). Generalised linear modelling further identified an optimal set of four markers, namely iC3b (alternative pathway), TCC (terminal pathway), MASP-2/C1Inh (lectin pathway), and the complement regulator properdin, which had a receiver operating characteristic predictive power of 0.796 (95% confidence interval = 0.664-0.905). Combinations of the classical pathway markers C4, C1q, and C1s/C1Inh were poorly predictive of long COVID. These findings demonstrate that activation of the lectin complement pathway, which occurs upstream of the alternative and terminal pathways and can be inhibited therapeutically, is a salient feature of long COVID.

Gout is associated with the upregulation of triggering receptor expressed on myeloid cells-1 (TREM-1) and soluble TREM-1 (sTREM-1). Cell activation signalling induced by monosodium urate (MSU) crystals and TREM-1 signalling both converge on spleen tyrosine kinase (Syk). The aim of this study was to decipher the role of the TREM-1 peptidomimetic inhibitor LP17, as well as Syk inhibitor, and their interaction during MSU-induced cell inflammation, focusing on NLRP3 inflammasome activation, IL-1β production and pyroptosis. In MSU-activated cells, both LP17 and Syk inhibitor (iSyk) significantly reduced the secretion of IL-1β and the release and activity of caspase-1. LP17 changed the phosphorylation of Syk, indicating that inhibition of TREM-1 modulates the activation state of Syk. Both LP17 and iSyk reduced the level of NLRP3-induced apoptosis-associated speck-like protein (ASC) transcripts and MSU-induced immunolabelling of ASC. Under confocal immunomicroscopy, TREM-1 in MSU-crystal-activated cells was localised to the same perimembranal compartment with NLRP3 inflammasome; inhibition of TREM-1 hindered the colocalisation of Syk with ASC. These results were corroborated by use of the in vitro ASC oligomerszation assay that showed that blocking TREM-1 induced Syk redistribution from ASC complexes, indicating that LP17 can repress the ability of Syk to incorporate into the forming ASC speckle. Additionally, unlike iSyk, LP17 hampered MSU-induced cleavage of gasdermin D, the hallmark of pyroptosis. Together, our findings suggest that blocking TREM-1 may prove beneficial as a novel strategy in the treatment of gout as well as other inflammasome-mediated diseases.

Eosinophils are multifunctional granulocytes that participate in tissue homeostasis, host defence, inflammation, and repair. Their activities are now known to extend beyond type-2 immunity and include the release of diverse cytokines and growth factors, such as IL-4, IL-13, TGF-β, IL-1β, GM-CSF, and TNF-α, together with context-dependent immunomodulatory, cytotoxic, and pro-remodelling functions. Recent advances highlight the importance of tissue imprinting and microenvironmental cues in shaping eosinophil phenotypes, revealing substantial functional plasticity and transcriptional diversity across physiological and pathological settings. Here we synthesise essential concepts in eosinophil biology and provide an overview of the most widely used approaches for visualising, isolating, and functionally characterising these cells, emphasising methodological strengths, limitations, and common artefacts. We further outline how transcriptomic and proteomic tools have refined the understanding of eosinophil phenotypes and their relevance to disease, including allergy, infection, tissue repair, and cancer. Overall, we provide a resource for basic and clinical investigators who are not currently working in eosinophil biology, but might be attracted to this multidisciplinary area in view of many recent exciting developments.

Ovarian cancer remains one of the deadliest gynaecological cancers due to its often-late diagnosis and the absence of specific symptoms in the early stages. Beyond genetic alterations, the tumour microenvironment, including the vaginal microbiota, plays a decisive role in tumour progression. Recent studies have highlighted the involvement of microbial imbalance 'dysbiosis' in ovarian carcinogenesis, particularly through interactions with the immune system and the modulation of local inflammatory pathways such as Th17-related pathways. In a state of 'eubiosis,' the vaginal microbiota, dominated by Lactobacillus species, plays a protective role by producing lactic acid, maintaining an acidic pH, and preventing infections. Conversely, dysbiosis, characterised by a decrease in lactobacilli and an increase in opportunistic bacteria such as Gardnerella, Atopobium and Prevotella, promotes chronic inflammation through Toll-like receptor signalling, stimulates the production of IL-6, IL-8 and TNF-α, thereby creating a pro-tumour immune microenvironment conducive to tumour development. The complex interactions of the microbial flora, mucosal immunity, and tumour cells could explain the association between vaginal microbiota and ovarian cancer. This review highlights these mechanisms and emphasises the potential of vaginal microbiota as a tool for early detection and improved diagnosis of ovarian cancer. A better understanding of this microbe-host dialogue could pave the way for new prevention and detection strategies.

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionised the treatment of hematologic malignancies, achieving durable and robust responses. However, the application of CAR-T cells in solid tumours remains limited by a complex network of barriers, most notably poor tumour infiltration. The key obstacles include mismatch between chemokines and receptors, abnormal tumour vasculature, immunosuppressive cellular populations (such as myeloid-derived suppressor cells, tumour-associated macrophages and regulatory T cells), dense network of cancer-associated fibroblasts and extracellular matrix, T cell dysfunction and exhaustion, metabolic limitations within the tumour microenvironment, tumour heterogeneity and transport limitations related to tumour location. By integrating mechanistic insights with innovative bioengineering and combination approaches, this review systematically elaborates on the factors that limit the infiltration of CAR-T cells and emphasises transformation strategies for improving the efficacy, durability and invasiveness of treating solid tumours.

Intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19) have an increased risk of bacterial coinfections, including ventilator-associated pneumonia (VAP), bloodstream infections (BSI) and catheter-associated urinary tract infections (CA-UTI). The objective was to investigate the prevalence, risk factors and spectrum of bacterial coinfections in patients with COVID-19 admitted to the ICU. It is a single-centre retrospective cohort study. Data from 201 patients with COVID-19 admitted to the University Clinical Intensive Care Hospital in Bialystok, Poland, between March 2020 and July 2021 were analysed. The prevalence of coinfections, risk factors and causative agents were assessed. Objective comparisons of data were performed by evaluating related studies and reviews. Bacterial coinfections developed in 70% of the 201 patients studied. The most frequent types were VAP, occurring in 47.5% of patients with bacterial coinfections, BSI and CA-UTI. Prolonged ventilatory support (mean duration of 13.3 days in the bacterial coinfection group) and prolonged ICU stay (mean of 15.3 days) were associated with an increased risk of these infections. The predominant pathogens were Klebsiella pneumoniae and Staphylococcus aureus, with Klebsiella pneumoniae extended spectrum beta-lactamases (ESBL) being the most frequently isolated pathogen after 48 h of ICU admission, detected in 121 instances. Bacterial coinfections are common in COVID-19 patients in the ICU and are associated with specific risk factors and pathogens. Vigilant monitoring, antimicrobial stewardship and infection prevention measures are needed to improve patient outcomes.

This study aimed to characterise the expression and functional heterogeneity of CD49f across CD4+ T cell subsets in human peripheral blood, and to investigate alterations in regulatory T cells (Tregs) and CD4+ T cells in patients with systemic lupus erythematosus (SLE), together with their clinical relevance. A total of 43 newly diagnosed, treatment-naïve SLE patients and 21 age- and sex-matched healthy controls were enrolled. Peripheral blood mononuclear cells were analysed by flow cytometry to assess CD49f expression in CD4 + FoxP3+ Tregs and non-Treg CD4+ T cells. Phenotypic and function-related markers were compared between CD49f + and CD49f- subsets. IL-10 production was evaluated as a functional readout in CD49f-defined Treg subsets. Associations between CD49f-related populations and clinical parameters were analysed, and receiver operating characteristic (ROC) curve analysis was performed to explore their potential clinical relevance. CD49f expression was higher in CD4 + FoxP3+ Tregs than in other CD4+ T cells. CD49f + CD4+ T cells exhibited increased CD226 and decreased CD45RA expression, consistent with an activated phenotype. CD49f + Tregs were enriched in the CD45RA-FoxP3int subset and showed higher CD226 but lower GZMB and Helios expression, indicating attenuated suppressive phenotypic features. In healthy controls, CD49f + Tregs displayed significantly higher IL-10 production than CD49f- Tregs, whereas this functional distinction was lost in SLE patients. The proportions of CD49f + subsets were significantly increased in SLE and correlated with multiple clinical indicators. ROC analysis revealed moderate discriminative performance of CD49f-related subsets, with AUC values ranging from 0.640 to 0.786. In conclusion, CD49f identifies distinct phenotypic and functional states within CD4+ T cells and Tregs. CD49f + CD4+ T cells exhibit activation features, while CD49f + Tregs show phenotypic attenuation accompanied by functional heterogeneity that is preserved in health but disrupted in SLE. Increased CD49f expression in SLE reflects immune imbalance and suggests potential value as a cellular immunological marker rather than a standalone diagnostic tool.

Over the past several decades, cure rates for paediatric hematologic malignancies have improved due to advances in cancer therapy. However, numerous obstacles limit the therapeutic efficacy of paediatric solid tumours, including the tumour's immunosuppressive microenvironment and the lack of specific tumour antigens for targeted therapy. Cancer vaccines, a form of immunotherapy, have been under development for more than half a century. Advances in immunology, materials science, sequencing technologies and bioinformatics have revolutionised cancer vaccine development, achieving substantial success in the prevention and treatment of solid tumours. Despite these achievements, the application of cancer vaccines developed for adults is not fully transferable to paediatric solid tumours because of differences in immune status and metabolic capacity. In clinical practice, most solid tumour vaccines designed for adults are applied directly to paediatric patients without modifications tailored to the unique features of the paediatric immune system. Limited attention has been given to designing cancer vaccines with improved efficacy and reduced toxicity for children and infants. This review discusses paediatric solid tumour vaccines from the immune system against tumour to different antigen types of cancer vaccines, illustrating the unique cancer-immunity cycle of young people and some potential strategies for vaccine modification. Additionally, it discusses the application of paediatric solid tumour vaccines through clinical trial data for conditions such as neuroblastoma, brain tumours and sarcomas. Challenges and potential solutions for enhancing vaccine efficacy, minimising side effects and broadening clinical applications are also addressed.

Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, characterised by rapid progression, extensive heterogeneity, and poor outcomes despite surgery, radiotherapy, and temozolomide (TMZ). A subpopulation of glioblastoma stem cells (GSCs) with self-renewal and multi-lineage differentiation capabilities drives tumour initiation, progression, recurrence, and therapeutic resistance. GSCs evade conventional treatments via enhanced DNA repair, multidrug efflux, activation of survival pathways, epigenetic reprogramming, and entry into quiescent states. Moreover, these cells utilise key immune escape mechanisms, such as downregulation of major histocompatibility complex molecules and the secretion of immunosuppressive factors, to escape detection and destruction by the immune system. Evidence suggests that transformed neural stem cells are a likely source of GSCs, with key survival networks including EGFR, FGFR, HGFR, and PI3K/AKT/mTOR signalling. Their phenotypic plasticity and adaptability to the tumour microenvironment further complicate eradication. Stem cell-based strategies utilising NSCs, MSCs, haematopoietic stem/progenitor cells, or induced pluripotent stem cells can effectively deliver immunomodulators to counteract these immune evasion mechanisms, exploiting tumour tropic migration to deliver therapeutic payloads into hypoxic and infiltrative niches. Approaches such as suicide gene therapy, oncolytic virus delivery, and CXCL12-CXCR4 axis modulation aim to target both proliferative and dormant GSCs. Preclinical studies demonstrate promising efficacy, yet challenges remain, including safety concerns, variability in outcomes, and the limited translational relevance of current models. This review provides a concise overview of GSC biology, resistance mechanisms, and emerging stem cell-based interventions, highlighting opportunities and obstacles in developing effective therapies for GBM.