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关键词： 结核感染T细胞斑点试验   白细胞介素-2   干扰素-γ   活动性肺结核   诊断效能  

摘要： 目的 探讨结核感染T细胞斑点试验(***)联合细胞因子白细胞介素-2(IL-2)、干扰素-γ(IFN-γ)对活动性肺结核(ATB)与非ATB的鉴别诊断价值。方法 以2021年2月-2024年3月河北省胸科医院收治的186例肺结核(TB)患者为研究对象,以痰MTB培养检查结果为金标准,将患者分为ATB组(n=92)及非ATB组(n=94),对所有患者进行***检测。收集并比较两组患者一般资料,将***、IL-2和IFN-γ作为因变量,临床咳嗽、发热症状作为自变量进行分层回归分析,分析临床特征对***、IL-2和IFN-γ的影响。应用主成分分析(PCA)法和偏最小二乘判别分析(PLS-DA)法评估***联合细胞因子IL-2、IFN-γ对ATB与非ATB的鉴别诊断价值。接收者操作特征(ROC)曲线检验***、IL-2和IFN-γ和预测模型的效能。结果 两组患者在咳嗽、发热、IL-1β、IL-2、IL-6、IL-8和IFN-γ方面差异存在统计学意义(P<0.05)。临床咳嗽、发热症状均会对***、IL-2和IFN-γ存在统计学正向关联(P<0.05)。PCA模型和PLS-DA模型结果显示,ATB和ATB患者个体差异均较小,两组均可明显聚类,2组可显著鉴别。联合模型的曲线下面积(AUC)最高(P<0.05),为0.913(0.875～0.950),其敏感度为90.24%,特异度为74.54%。结论 ***联合IFN-γ和IL-2诊断ATB和非ATB具有较高的准确度和敏感度,可作为ATB的辅助诊断方法,具有较高的临床价值。

摘要： Poor infiltration of CD8+ T cells and dysregulation of major histocompatibility complex 1 (MHC-I) confer resistance to anticancer immunotherapies. Inhibition of the epigenetic regulator lysine-specific demethylase 1 (LSD1) has been shown to increase CD8+ T cell infiltration in head and neck squamous cell carcinoma (HNSCC). In this study, we aimed to elucidate the mechanisms of LSD1 inhibition in antitumor immunity in HNSCC to aid in the development of effective therapeutic strategies. LSD1 inhibition in syngeneic and chronic tobacco carcinogen-induced HNSCC mouse models increased recruitment of activated dendritic cells (DCs), as well as CD4+ and CD8+ T cells, and expression of interferon-gamma (IFNγ) in CD8+ T cells, CXCL9 in DCs, and CXCR3 in CD4+ T cells. Humanized HNSCC mice and patient data validated the inverse correlation of KDM1A with DC markers, CD8+ T cells, and their activating chemokines. Kdm1a knockout in mouse HNSCC and LSD1 inhibitor treatment of human HNSCC cells co-cultured with human peripheral blood mononuclear cells resulted in MHC-I upregulation in cancer cells. LSD1 inhibition promoted CD8+ T cell activation via a DC-dependent mechanism and induced efficient antigen presentation in CD8+ T cells. LSD1 inhibition increased H3K4me2 at the promoters of DC-related markers (BATF3 and CXCL9), T cell markers (CXCR3), and MHC-I (HLA-A). Overall, LSD1 inhibition in tumor cells upregulates MHC-I expression and stimulates CXCL9 secretion by DCs to enhance antigen presentation and promote CD8+ T cell activation via the CXCL9-CXCR3 signaling axis, resulting in increased IFNγ production. This may have implications for treating poorly immunogenic and immunotherapy-resistant cancers.

摘要： OBJECTIVE:Childhood obesity may impact the risk of islet autoimmunity (IA). The trajectory of BMI through childhood resembles the early peak incidence of first-appearing autoantibodies against insulin (IAA-first) but not GAD65 (GADA-first). We studied whether a child's BMI can impact the age-related risk of first-appearing IA phenotypes. RESEARCH DESIGN AND METHODS:We identified 7,724 children at risk for IA with at least three BMI measurements in The Environmental Determinants of Diabetes in the Young (TEDDY) study. We modeled the risk of IAA-first, GADA-first, and IA overall on a child's BMI z score and change in BMI during infancy (age 2 weeks to 1.5 years, n = 7,724), early childhood (age 1.5-8.5 years, n = 6,396), and puberty (age 8.5-15 years, n = 4,732) using joint modeling of longitudinal BMI and time-to-event IA. RESULTS:An infant's BMI z score was not associated with IA risk before 18 months of age (n = 185, hazard ratio [HR] 1.03 [95% CI 0.88, 1.19]). In contrast, a child's BMI correlated with an increased risk of IA from 1.5 to 8.5 years of age (n = 470, HR 1.20 [95% CI 1.04, 1.32]) and from 8.5 to 15 years of age (n = 209, HR 1.27 [95% CI 1.09, 1.49]). No interactions with first-appearing IA phenotypes were observed. However, high BMI z score (SD >0.5) from age 9 months increased the risk of IA in early childhood, specifically for children with HLA-DR4/4 or HLA-DR4/8 and not with HLA-DR3/3 or HLA-DR3/4 (HLA * BMI interaction, P < 0.005). CONCLUSIONS:The contribution of BMI to risk of IA during early childhood is dependent on the HLA-DR-DQ genotype more so than the first-appearing IA phenotype.

关键词： Immune checkpoint inhibitors   immune-related cutaneous adverse events   psoriasiform rash   IL-17A   secukinumab  

关键词： allergen-specific immunotherapy   birch pollen allergy   CD8+T cells   DNA methylation   epigenome-wide DNA methylation study   HLA   NK cells  

摘要： Background Until now, no study has investigated the impact of allergen immunotherapy (AIT) on genome-wide DNA methylation in a longitudinal set-up. Herein, we investigated whether differences in DNA methylation occur in birch pollen allergic patients undergoing 6 months of birch pollen AIT, assessed alterations in methylation-based blood cell type composition, and correlated DNA methylation to serological AIT *** We performed genome-wide DNA-methylation analysis on bisulfite-converted DNA derived from whole blood samples of 16 birch pollen-allergic patients (pre-/post-birch pollen AIT) and 15 placebo (pre-/post-placebo treatment).Results Our analysis identified cg22187251, located within a regulatory region upstream of the glucosaminyl (N-acetyl) transferase 2 (GCNT2) gene and cg22336863 upstream of the transcription start site of actin binding rho activating protein (ABRA), as hypermethylated. Functional assays revealed that these regions exhibit methylation-dependent promoter and enhancer activities. We identified differentially methylated positions within the HLA gene complex, and an AIT-specific increase of CD8+ T cell populations accompanied by a decrease in natural killer (NK) cell proportion. Strong to moderate correlations with clinical biomarkers (such as specific IgG4) were observed for 42% of the top 100 differentially methylated *** GCNT2 and ABRA are implicated in Rho-signaling, a pathway involved in Th2 differentiation. GCNT2 modulates the SMAD-dependent TGF-beta pathway, indicating a role in mediating AIT-induced immunotolerance. This is the first longitudinal study investigating DNA methylation changes induced by birch pollen AIT.

关键词： Anti–IL-13 antibody   Eosinophilic esophagitis (EoE)   Interleukin 13 (IL-13)   Transcriptome  

摘要：

关键词： ADAMTS4   CAP-LAMP2b engineering   cartilage repair   extracellular vesicles   human umbilical cord mesenchymal stem cells   inflammation   regenerative medicine  

摘要： Extracellular vesicles (EVs) from mesenchymal stem cells hold therapeutic promise for inflammatory and degenerative diseases; however, limited delivery and targeting capabilities hinder their clinical use. In this study, we sought to enhance the anti-inflammatory and chondroprotective effects of EVs through CAP-LAMP2b (chondrocyte affinity peptide fused to an EV membrane protein) engineering and gene editing hybrid vesicle formation. Human umbilical cord MSCs (hUCMSCs) were characterized via morphology, immunophenotyping, and trilineage differentiation. EVs from control and CAP-LAMP2b-transfected hUCMSCs were fused with liposomes carrying CRISPR-Cas9 ADAMTS4 gRNA. DiI-labeled EV uptake was assessed via fluorescence imaging. CAP-LAMP2b was expressed in hUCMSCs and their EVs. EVs exhibited the expected size (~120 nm), morphology, and exosomal markers (CD9, CD63, CD81, HSP70). CAP-modified hybrid EVs significantly enhanced chondrocyte uptake compared to control EVs and liposomes. IL-1β increased ADAMTS4 expression, whereas CAP-LAMP2b-ADAMTS4 EVs, particularly clone SG3, reversed these effects by reducing ADAMTS4 and restoring aggrecan. Western blotting confirmed suppressed ADAMTS4 and elevated aggrecan protein. CAP-LAMP2b-ADAMTS4 EVs, therefore, showed superior uptake and therapeutic efficacy in inflamed chondrocytes, attenuating inflammatory gene expression and preserving matrix integrity. These results support engineered EVs as a promising cell-free approach for cartilage repair and osteoarthritis treatment.

关键词： Alopecia areata   Interleukin-2   JAK inhibitor   Regulatory T cells   Sequential immunotherapy   Sustained remission   Tofacitinib  

摘要： Background Alopecia areata (AA) is a chronic autoimmune condition that causes non-scarring hair loss and often leads to significant psychosocial distress. Although Janus kinase (JAK) inhibitors such as tofacitinib are effective, relapse after stopping treatment remains a major challenge. New evidence indicates that low-dose interleukin-2 (IL-2) may help maintain remission by increasing regulatory T cells, which can restore immune *** This proof-of-concept study aimed to evaluate the efficacy of sequential immunotherapy combining tofacitinib and low-dose IL-2 in inducing sustained remission for AA patients after treatment *** A monocentric, retrospective case series was conducted at Xiangya Hospital, China, from September 2022 to May 2025. The IL-2 regimen comprised subcutaneous injections (0.5-1 million IU/day for 5 consecutive days per cycle), repeated every 3 weeks for two to three cycles. Tofacitinib was tapered and discontinued post-IL-2 therapy. Clinical outcomes, including relapse-free survival and safety, were monitored *** Four refractory AA patients (median follow-up: 32.5 months) with complete hair regrowth (SALT = 0) after >= 6 months of tofacitinib received adjunctive IL-2. Three patients maintained complete remission for 11-20 months after treatment cessation, while one experienced localized recurrence at 5 months but achieved control with low-dose tofacitinib maintenance. No adverse events were *** Sequential tofacitinib and low-dose IL-2 therapy may reestablish immune tolerance, offering a potential strategy for drug-free remission. Larger trials are needed to confirm efficacy and optimize protocols.