Immunology最新文献

Rheumatoid arthritis (RA) causes long-term functional disability, aggravating physical and mental stress to patients. However, the dynamic pathogenesis before RA onset remains unclear. Here we examined the associations between 2923 plasma proteins and incident RA in the UK Biobank cohort. Over a 15-year follow-up period, 433 RA cases were identified, revealing 460 significant protein-RA associations. These RA-related proteins were predominantly involved in immune responses, such as leukocyte migration, T cell activation, and lymphocyte activation. Sixty five proteins were significantly associated with both long-term and near-term risk of RA. Among them, 26 proteins exhibited changes as early as over 15 years prior to RA onset with progressively fluctuating, such as IL6 and IFI30. Others, such as CDCP1 and TGFA, showed inconsistent fluctuation patterns, while proteins like GDF15 and EDA2R began to fluctuate closer to the onset of RA. Furthermore, these proteins demonstrated robust predictive performance, with an area under the curve (AUC) of 0.818 in the training set and 0.766 in the test set. When combined with demographic measures, the predictive model showed further improvement, achieving an AUC of 0.871 in the training set and 0.919 in the test set. Our findings characterise plasma protein fluctuation trajectories over 15 years before RA onset and deepen our understanding of early-stage pathogenesis.

This study aims to explore the role of CD39 in peripheral blood T cells and its alterations in patients with systemic lupus erythematosus (SLE), focusing on its potential for clinical diagnosis. Peripheral blood samples were collected from 58 newly diagnosed untreated SLE patients and 48 healthy controls. Flow cytometry was used to evaluate CD39 expression in CD4⁺ T cell subsets (TEMRA, N, EM, CM) and Treg/non-Treg populations. The expression of CD39 and related molecules (VNN2, CD226, CD62L, TIM3, HLA, GZMB) was analysed in peripheral blood mononuclear cells (PBMCs). The correlation between CD39⁺ T cell subsets and clinical markers was assessed, and the diagnostic value of CD39⁺ subsets was evaluated using receiver operating characteristic (ROC) curve analysis. CD39 expression was significantly elevated in CD4⁺ T cells, especially in TEMRA and non-Treg subsets. CD39⁺ T cells exhibited higher levels of effector molecules such as TIM3, CD226, HLA, VNN2 and GZMB, while CD62L expression was lower. The proportion of CD39 related T cells in SLE patients was significantly higher compared to healthy controls, with significant correlations to clinical markers like anti-SSB antibodies and complement C4. ROC analysis revealed that CD39⁺ T cell subsets, particularly in N and non-Treg cells, showed potential for diagnosing SLE. CD39⁺ T cells are involved in immune dysregulation in SLE, and their increased presence and subset distribution suggest their potential as diagnostic markers for SLE.

Leukocyte-specific protein 1 (LSP1) is an F-actin-binding protein involved in immune cell motility and cytoskeletal rearrangement. Although LSP1 has been extensively studied in neutrophils and macrophages, its role in dendritic cells and tumour surveillance remains poorly understood. Here, we demonstrate that LSP1 deficiency in mice leads to increased growth of B16-OVA melanoma, accompanied by reduced survival. Flow cytometry and histological analysis revealed lower total leukocyte content in the tumour microenvironment (TME) in LSP1 knockout (KO) mice compared to wild-type (WT) mice, and a significant reduction in CD8⁺ T cells and CD103⁺ dendritic cells (DCs), as well as in additional immune cell populations, in tumour-draining lymph nodes of LSP1 KO mice. In vivo, DCs from LSP1 KO mice exhibited impaired antigen uptake and transportation to the tumour-draining lymph node and a reduced in vitro capacity to activate naïve CD8⁺ T cells. These defects correlated with diminished in vitro and in vivo CD8⁺ T cell priming and activation in LSP1-deficient mice. Cytokine profiling of tumour homogenates from LSP1 KO mice revealed a complex inflammatory milieu, with elevated levels of both pro- and anti-tumoural cytokines, including IL-1β, TNF-α, IL-10, IL-17A, IFNβ IL-23, IL-27 and GM-CSF. Our findings suggest that LSP1 plays a critical, cell-intrinsic role in both DC and CD8⁺ T cell function, although we cannot exclude the possible role of other leukocyte populations. Its absence promotes tumour progression by disrupting key immune responses in the TME.

This study aims to assess the distribution of mucosal-associated invariant T (MAIT) cells across CD3+ T cell subsets in human peripheral blood and investigate their changes in patients with primary Sjögren's syndrome (pSS), exploring their potential clinical implications. Peripheral blood from 39 pSS patients and 45 healthy controls was analysed. CD3+ T cells were categorised into four subsets: CD4+CD8−, double-positive (DP), double-negative (DN), and CD8+CD4−. MAIT cells (CD161++TCRVα7.2+) were identified using flow cytometry. Proportions and absolute counts of MAIT cells were compared between pSS patients and controls. Supplementary experiments were conducted on the peripheral blood of 15 pSS patients and 17 healthy controls to analyse the expression of GZMB and perforin in MAIT cells and their four subpopulations (CD4+ MAIT, CD8+ MAIT, DN MAIT, and DP MAIT). MAIT cell-related parameters were correlated with clinical indices, and their diagnostic value was evaluated using receiver operating characteristic (ROC) curves. The proportion and absolute count of MAIT cells were significantly reduced in pSS patients compared to healthy controls. In particular, MAIT cell levels were markedly lower in the DN and CD8+CD4− subsets. Additionally, the absolute counts of MAIT cells were significantly decreased in the DP, DN, and CD8+CD4− subsets, whereas no significant change was observed in the CD4+CD8− subset. Compared with healthy controls, the proportion of GZMB+ cells in the CD8+ MAIT and DN MAIT subpopulations of pSS patients increased. The percentages of MAIT cells within CD3+ T cells were negatively correlated with inflammatory markers, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and anti-SSB antibodies. Notably, MAIT cells in the DN subset were also positively correlated with complement C4 levels. MAIT cell proportions and counts vary across CD3+ T cell subsets, showing significant reductions in pSS patients. These findings highlight the potential role of MAIT cells as a diagnostic biomarker, given their strong associations with clinical disease markers in pSS.

Tuberculosis (TB) remains a global health burden, particularly because of the limited efficacy of the Bacillus Calmette-Guérin (BCG) vaccine against adult pulmonary TB. To improve immunogenicity, we developed a recombinant BCG strain expressing the M. tuberculosis -specific antigen Rv1507A (rBCG_Rv1507A) and evaluated its immune-enhancing potential. rBCG_Rv1507A-infected human PBMCs and murine macrophages exhibited enhanced co-stimulatory marker expression and Th1-skewed cytokine profiles in vitro. The vaccine stimulated the expansion of T follicular helper (TFH) cells and both central and effector memory T cells. Intratracheal immunisation induced systemic and mucosal antibody responses, localized memory B cell formation, and enrichment of lung-resident memory T cells in vivo. Importantly, rBCG_Rv1507A promoted macrophage apoptosis and suppressed autophagy, which may support cross-antigen presentation. Furthermore, it induces features of trained immunity, including hematopoietic progenitor expansion and metabolic reprogramming of macrophages. These immunological enhancements were compartmentalized to the lungs, the primary site of TB infection, due to mucosal delivery. Collectively, rBCG_Rv1507A demonstrated potential as a next-generation TB vaccine by integrating durable adaptive memory with innate immune training. However, further studies are required to confirm its protective efficacy.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterised by chronic inflammation and immune dysregulation, with neutrophils playing a critical role in disease pathogenesis. In this study, we elucidated the involvement of the CXCL2-PI3K/AKT/NF-κB signalling axis in the abnormal activation of neutrophils in SLE using transcriptome analysis and functional experiments. Transcriptomic profiling revealed that CXCL2 expression is significantly upregulated in SLE patients, contributing to the activation of key inflammatory pathways and the expression of pro-inflammatory cytokines and chemokines. In vitro and in vivo experiments confirmed that CXCL2 promotes the transcription of inflammatory factors by activating the PI3K/AKT/NF-κB pathway, and inhibitors targeting this signalling axis effectively reduced inflammation. Furthermore, neutrophils from SLE patients exhibited a ‘pre-activated’ state under CXCL2 stimulation, potentially due to epigenetic or metabolic alterations. The functional relevance of CXCL2 was further validated in vivo, where knockout of CXCL2 or depletion of neutrophils reduced tissue damage and inflammatory responses. This study highlights the importance of the CXCL2-PI3K/AKT/NF-κB signalling axis in SLE and suggests that targeting CXCL2 or neutrophil-specific markers could provide novel therapeutic strategies for managing SLE. Future research should explore the heterogeneity of neutrophil subpopulations in SLE and the role of metabolic reprogramming in exacerbating inflammation, further refining potential targeted therapies.

Human papillomavirus type 16 (HPV16) E6 and E7 are oncogenic proteins that are overexpressed following viral genome integration into the chromosomal DNA of infected mucosal epithelial cells, contributing to viral immune evasion and carcinogenesis. Epithelial cells can shed large extracellular vesicles (LEVs) that may modulate immune responses. We hypothesise that LEVs shed from epithelial cells expressing E6 and E7 modulate CD8⁺ T cell priming by the skin-local antigen presenting cells, the Langerhans cells (LCs). LEVs were isolated from control and E6/E7-expressing murine epithelial PDV cells. PDV-E6/E7 cells shed threefold more LEVs than control PDV cells in vitro. Murine LC ‘like’ cells were differentiated in vitro, co-cultured with LEVs, and assessed for antigen presentation, co-stimulatory molecule expression and cytokine production. We found that LCs co-cultured with Ctrl-LEVs demonstrated enhanced TAP1-dependent CD8 T cell priming, which was associated with increased co-stimulatory molecule and IL-12 expression. LCs co-cultured with E6/E7-LEVs failed to enhance TAP-1-dependent T cell priming and suppressed IL-12 production despite upregulating MHC-1 and co-stimulatory molecule expression. Our results show that LC priming of T cells is enhanced following treatment with Ctrl-LEVs whereas LEVs from HPV16 E6/E7 expressing cells suppress LC function. Functional impairment of LC priming of T cells by E6/E7-LEVs released in the epithelium may contribute to viral persistence in HPV16-infected skin.

Interleukin-4 (IL-4) drives Th2 polarisation and allergic inflammation, yet the epigenetic mechanisms regulating Il4 transcription in CD4⁺ T cells remain unclear. While STAT6 and GATA3 are canonical transcriptional regulators, lysine-specific demethylase 5A (KDM5A), an H3K4-specific demethylase, has not been linked to Th2 immunity. Here, we investigate KDM5A's role in IL-4 production and allergic airway disease (AA). Using DO11.10 TCR-transgenic mice and CD4⁺ T cell-specific Kdm5a-knockout models, we assessed KDM5A's role in IL-4 transcription. Chromatin immunoprecipitation (ChIP)-qPCR evaluated H3K4 demethylation at the Il4 promoter. Cross-ELISA quantified IL-4 secretion, and ubiquitination assays analysed KDM5A stability. Lactobacilli-derived DNA (LgDNA) was administered to disrupt the USP7-KDM5A axis in AA models. The results showed that KDM5A deficiency abolished TCR activation-induced IL-4 production, impairing Th2 polarisation. Mechanistically, KDM5A maintained H3K4 hypomethylation at the Il4 promoter, facilitating STAT6/GATA3 recruitment. TCR signalling enhanced KDM5A promoter occupancy via USP7-mediated deubiquitination. USP7 stabilisation of KDM5A elevated H3K4 demethylation and IL-4 transcription, driving AA pathogenesis. LgDNA suppressed USP7 activity, reducing KDM5A promoter binding by 65% and airway inflammation by 72%. In summary, KDM5A acts as an epigenetic rheostat of Th2 immunity, where USP7-dependent stabilisation licenses STAT6/GATA3 access to the Il4 promoter during TCR activation. Targeting the USP7-KDM5A axis with LgDNA selectively suppresses pathogenic Th2 responses while preserving physiological IL-4 functions. Our findings define a novel epigenetic mechanism for allergic disease and establish microbiome-derived LgDNA as a precision therapeutic strategy.