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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： interleukin-1 receptor antagonists   antibodies   pericarditis, recurrent   autoantibodies   interleukin-1   antagonists  

关键词： human umbilical cord mesenchymal stem cells   extracellular vesicles   cartilage repair   inflammation   CAP-LAMP2b engineering   ADAMTS4   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 ADAMTS4 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 (similar to 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-1 beta 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.

关键词： immunotoxin   IL-33   ribotoxin alpha-sarcin   ILC2 cells   ST2 receptor   allergic response  

摘要： Allergies constitute one of the major health problems worldwide, increasing their prevalence in developed countries. To overcome this multifactorial disease, immunotherapy and the use of immune molecules, such as immunotoxins, have arisen as promising therapeutic tools. We have designed, produced, and characterized a new immunotoxin called IL-33 alpha S, encompassing the murine IL-33 (mIL-33) as the target domain and the ribotoxin alpha-sarcin as the toxic domain. IL-33 is a widely described alarmin that binds to the ST2 receptor of a variety of immune cells, including ILC2s, leading to Th2-derived inflammatory response, as occurs in allergic reactions. Both IL-33 alpha S and mIL-33 were successfully produced in the methylotrophic yeast Pichia pastoris and purified to homogeneity through affinity chromatography for their characterization. Both IL-33 alpha S and mIL-33 were able to specifically bind to ST2+ Raw 264.7 cells, and IL-33 alpha S kept the ribonucleolytic activity of alpha-sarcin, allowing IL-33 alpha S to exhibit cytotoxic effects against ST2+-targeted cells. In addition, IL-33 alpha S induced significantly less secretion of the Th2-linked cytokine IL-13 in comparison to mIL-33, suggesting steric interference produced by the presence of the alpha-sarcin. These results assess the potential therapeutic effect of this new immunotoxin against allergies, causing ST2-targeted cytotoxicity while avoiding the Th2 cytokine secretion.

关键词： C反应蛋白   原核表达   分子伴侣   单克隆抗体  

摘要： [目的]本研究旨在制备猪C反应蛋白（C-reactive protein， CRP）的单克隆抗体，为建立用于监测猪血清中CRP蛋白浓度的血清学方法提供生物材料。[方法]通过优化CRP基因并克隆至原核表达载体pET28a，并将分子伴侣质粒pTF16与重组质粒共转化并表达重组CRP蛋白，将该蛋白作为免疫原免疫BALB/c雌鼠，通过细胞融合、间接ELISA筛选，得到分泌抗重组CRP蛋白的杂交瘤细胞，制备单克隆抗体，进行效价测定及亚型鉴定，采用Western blot检测其特异性，进行生物素标记制备生物素标记单克隆抗体。[结果]成功构建重组质粒及重组表达载体，经细胞融合和亚克隆成功获得2株分泌抗重组猪CRP蛋白单克隆抗体的杂交瘤细胞，分别命名为CRP-Mab1和CRP-Mab2，两株杂交瘤细胞上清效价分别为1：409 600和1：204 800。Western blot结果显示，2株单克隆抗体均能与重组猪CRP蛋白特异反应。亚型鉴定结果显示，CRP-Mab1抗体轻链属于κ型，重链属于IgG1型，CRP-Mab2单克隆抗体轻链属于κ型，重链属于IgM型。进行生物素标记并获得标记的单克隆抗体CRP-Mab1-Bio，其效价可达1：12 800。[结论]成功制备2株针对重组猪CRP蛋白的单克隆抗体，并进行生物素标记，为猪CRP蛋白浓度检测及炎性情况监测方法的开发提供了重要的生物材料。