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关键词： span>biological therapyJanus kinase inhibitorscyclosporinesurveillancescreeninginflammatory skin diseasestuberculosistuberculin testinterferon-gamma release testhealth services researchpublic healthinfection  

摘要： Protein secretion plays a crucial role in maintaining immune homeostasis, yet the molecular interactions governing this process remain incompletely understood. While transcriptional and post-transcriptional regulation of protein expression is well characterized, the subcellular interactions between secreted proteins and trafficking machinery are less explored. To address this, we systematically mapped protein-protein interactions (PPIs) involved in the secretion of interleukin-2 (IL-2) from human T cells using proximity-based labeling coupled with mass spectrometry. Our analysis revealed significant enrichment of proteins associated with conventional secretory pathways, including ER-to-Golgi transport, protein folding, and vesicle-mediated trafficking. Functional validation confirmed that several of these proteins are critical for IL-2 secretion, underscoring their direct roles in cytokine processing. In addition, time-resolved profiling of PPIs and transcriptomic changes following T cell stimulation revealed dynamic remodeling of the cytokine secretion machinery, reflecting multilayered regulation at both the protein and gene expression levels. These findings offer a systems-level understanding of IL-2 secretion and identify new molecular components that can be targeted to modulate immune responses. This work provides a framework for dissecting complex secretory processes and has broad implications for therapeutic strategies in immune-related diseases.

关键词： hemodialysis   Interleukin-6   Tumor Necrosis Factor-alpha   left ventricular hypertrophy   echocardiography   chronic inflammation   cardiac remodeling   right ventricular dilation  

摘要： Background and Objectives: Cardiovascular disease remains the leading cause of mortality in end-stage renal disease, with systemic inflammation implicated in myocardial remodeling. We aimed to assess the associations between IL-6, TNF-alpha, and IL-1 beta and echocardiographic parameters of cardiac remodeling, including left ventricular mass (LVM), global longitudinal strain (GLS), interventricular septum (IVS), left ventricular end-diastolic diameter (LVEDD), and right ventricular diameter (RVD), in patients undergoing maintenance hemodialysis. This was a single-center retrospective observational study. Materials and Methods: In 58 maintenance hemodialysis patients (mean age 60.4 +/- 11.7 years;55% male), pre-dialysis serum cytokines (IL-6, TNF-alpha, IL-1 beta) and standard laboratory markers (C-reactive protein [CRP], albumin, hemoglobin) were measured. Echocardiography was performed under clinically stable conditions. Spearman correlations assessed relationships between cytokines and imaging parameters;multivariate linear regression identified independent predictors. Results: Median IL-6 was 7.36 pg/mL (interquartile range [IQR] 4.52-11.03), and median TNF-alpha was 9.35 pg/mL (IQR 7.9-12.57). IL-6 correlated positively with LVM (rho = 0.63, p < 0.001), RVD (rho = 0.53, p < 0.001), and CRP (rho = 0.52, p < 0.001). In contrast, TNF-alpha inversely correlated with LVM (rho = -0.36, p = 0.006). Multivariate regression showed IL-6 was independently predicted by LVM (p = 0.019) and RVD (p = 0.042), while TNF-alpha was predicted by age (p < 0.001), CRP (p = 0.038), and albumin (p = 0.012). Conclusions: In hemodialysis patients, IL-6 showed stronger associations with echocardiographic hypertrophy and dilation than TNF-alpha, supporting its role as a potential biomarker of subclinical cardiac ***-6 showed stronger correlations with echocardiographic remodeling markers compared with TNF-alpha and may warrant further investigation as a potential biomarker in thi

关键词： Amyotrophic lateral sclerosis   Th1 (IFN-gamma(+)CD4(+))/CD4(+)   Prognostic model   Machine learning   Neuroimmunology  

摘要： Background Th1 (IFN-gamma(+)CD4(+))/CD4(+) cells exacerbate the release of pro-inflammatory cytokines, contributing to neuronal death. It is proposed that the peripheral immune system plays a pivotal role in the pathophysiology of amyotrophic lateral sclerosis (ALS). This study aims to develop an interpretable machine learning model based on blood Th1/CD4(+) cells to predict rapidly progressive ALS. Methods We enrolled 564 patients with sporadic ALS who met the eligibility inclusion criteria for further analysis. Immune cells and cytokines were quantified using flow cytometric cell counting and a flow cytometry-based fluorescent bead capture assay. Multivariate Cox proportional hazards models and restricted cubic spline analyses were applied to estimate the correlation between Th1/CD4(+) cells and rapidly progressive ALS. The important variables identified through LASSO regression analysis were incorporated into the development of the machine learning model. Results The multivariate Cox proportional hazards model revealed that, compared to the low Th1/CD4(+) group (Th1/CD4(+) < 16.21), the high Th1/CD4(+) group (Th1/CD4(+) >= 16.21) was positively associated with the rate of ALS progression (HR: 1.90, 95% CI: 1.34-2.70). Th1/CD4(+) is also associated with the decline in forced vital capacity (r = 0.11, P = 0.01). The machine learning model was built using Th1/CD4(+) in combination with the other 4 features. Xgboost performed best in the validation cohort, achieving an AUC of 0.804 and a G mean of 0.756. Conclusions Th1/CD4(+) (with an optimal cutoff value of 16.21) was established as an independent risk factor for rapid progression in ALS. The machine learning model incorporating Th1/CD4(+) demonstrated strong predictive performance. Trial registration The prospective cohort study is registered with the Chinese Clinical Trial Registry (ID: ChiCTR2400079885) (http://***/).

关键词： frequency distribution   global frequency browser   heatmap   HLA   HLAtools   informatics   SSHAARP  

摘要： The highly polymorphic HLA genes inform susceptibility and resistance to infectious and autoimmune diseases and cancers and are key for successful solid-organ and stem-cell transplantation therapies. Over 41,000 HLA alleles are known and are unevenly distributed across the human population. Here, we describe HLAtools, Searching Shared HLA Amino-Acid Residue Prevalence (SSHAARP) and the Global Frequency Browser (GFB), new informatic tools developed to facilitate working with HLA data and visualizing the global distribution of HLA variants in human populations. HLAtools is an R package that consumes static resources for HLA alleles and sequences and makes these data locally computable alongside data-query, data-customization and data-analysis functions. The package further includes new reference datasets that dissect and catalogue HLA regions and HLA gene structures and provide insight into the organization of HLA pseudogenes and gene fragments. SSHAARP is an R package that describes the frequency distributions of individual HLA haplotypes, alleles and amino-acid motifs as global heatmaps. Allele frequency maps for more than 800 HLA alleles can be browsed using the GFB web and mobile applications. HLAtools and SSHAARP are available from the Comprehensive R Archive Network, and the GFB apps are available on GitHub.

关键词： IL-38   inflammation   lupus  

摘要： Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown origin. Recent evidence has linked butyrophilin 3A1 (BTN3A1) to immune dysregulation. This study was to elucidate the relationship of BTN3A1 in SLE. Expression of BTN3A1 in plasma and peripheral blood mononuclear cells from SLE patients and healthy controls explored the association between BTN3A1 and SLE. We found that BTN3A1 mRNA, plasma levels, and expression in CD4+ T cells were significantly elevated in SLE patients. In BTN3A1 gene knock-in (BTN3A1KI) mice, inflammation and lupus-like manifestations occurred, including increased proportions of Th1, Th2, and Th17 cells, decreased Treg cells, elevated levels of inflammatory cytokines and anti-dsDNA antibodies, renal injury, and suppressed IL-38 serum levels. Intraperitoneal injection of IL-38 in pristane-treated BTN3A1KI mice notably alleviated these pathological changes. Mechanistic investigations revealed that CD4+ T cells and the ferroptosis pathway were closely associated with the effects mediated by the BTN3A1-IL-38 axis. In vitro experiments showed that IL-38 stimulation reduced proliferation, apoptosis, and decreased the expression of ferroptosis-related proteins, Fe2(+), glutathione, and malondialdehyde in CD4+BTN3A1+/+ T and BTN3A1+/+ Jurkat T cells. Overall, BTN3A1 plays a crucial role in SLE pathogenesis by regulating CD4+ T cell function.

摘要： Amino acid variations in the HLA molecule may serve as part of serologic epitopes (residues determining epitopes: DEP) detected by allo-antibodies. In current clinical histocompatibility practices, the presence of anti-HLA donor-specific antibodies (DSA) is assessed by solid phase (SP) tests with single antigen bead (SAB) panels. The antigenic risk is assessed based on the mean fluorescence intensity (MFI) values corresponding to each SAB via virtual crossmatch (VXM). To improve the accuracy of the VXM, new Associated Antigens were proposed based on DEPs;however, the antigenicity of some DEPs remained uncertain. In the current study, highly complex reactive sera were selected, and the complexity was reduced by adsorption with magnetic beads or lymphocytes followed by acid/neutralisation processes. As a proof of concept, a patient's serum was enriched with SAB coated with HLA-A*01:01. The eluate was tested using SP-SAB and showed reactivity with the antigens HLA-A1, -A9 (excluding A2403), -A80, -B12 and -B76. This allowed for validation of the antibody enrichment process and identification of the serological equivalency of DEPs 167G and 167S shared by these antigens. We identified broadly reactive sera being positive with the SAB HLA-B*35:12 (103V) and negative with the other SAB HLA-B35 (103L). Allo-antibodies were enriched by the adsorption/elution procedure with lymphocytes expressing HLA-B*35:12 and with SABs coated with HLA-B*57:01. The SAB assay using one of the eluates showed an almost identical cross-reactivity pattern: positive with all HLA-B SABs bearing 103V and no reactivity with SABs bearing 103L, suggesting that the enriched antibodies reacted with epitope(s) shared by HLA-B*35:12 and HLA-B*57:01. Additional reactivity was detected with the SABs HLA-A32, -A74 and -Cw3. This allowed for identification of putative epitope(s) containing residues 103V and 109L. Another serum with positive reactivity to the SAB HLA-B*35:02 showed reactivity to almost all HLA

摘要： HLA-G*01:64 differs from HLA-G*01:04:01 by one nonsynonymous nucleotide substitution in codon 107 in exon 2.