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关键词： 司美格鲁肽   缺氧复氧   心肌细胞   炎症   焦亡   经典途径   非经典途径  

摘要： 目的 探究司美格鲁肽对缺氧/复氧AC16人心肌细胞经典及非经典途径细胞焦亡的影响。方法 取对数生长期的AC16细胞,随机分为3组：对照组、缺氧/复氧模型组、缺氧/复氧加司美格鲁肽组。除对照组外，其余2组细胞均进行缺氧8 h、复氧12 h处理。CCK-8试剂盒检测细胞活性。ELISA试剂盒检测白细胞介素（interleukin,IL）-1β、IL-18。乳酸脱氢酶（lactate dehydrogenase,LDH）试剂盒检测细胞损伤情况。Western blot法检测细胞内半胱氨酸天冬氨酸蛋白酶（cysteine aspartate protease,Caspase）-1、Caspase-4、焦孔素D(Gasdermin-D,GSDMD)、核苷酸结合寡聚结构域样受体蛋白3(nucleotide-binding oligomerization domain-like receptor protein 3,NLRP3)蛋白表达。免疫荧光染色法观察各组细胞GSDMD阳性表达。透射电子显微镜观察各组AC16细胞细胞膜破损情况。结果 与对照组相比，缺氧/复氧组IL-1β、IL-18及LDH明显升高(P<0.01)，焦亡相关蛋白Caspase-1、Caspase-4、GSDMD及NLRP3表达均明显增加(P<0.01)，且免疫荧光染色法观察细胞GSDMD的荧光强度显著增加(P<0.01)。与缺氧/复氧组相比，缺氧复氧加司美格鲁肽组IL-1β、IL-18及LDH均明显降低(P<0.01)，焦亡相关蛋白Caspase-1、Caspase-4、GSDMD及NLRP3表达均显著降低(P<0.01)，且免疫荧光染色法观察细胞GSDMD的荧光强度明显降低(P<0.01)。结论 司美格鲁肽可能通过抑制Caspase-1和Caspase-4，抑制焦亡的经典途径和非经典途径，从而抑制心肌细胞焦亡，减少炎症因子释放，减轻缺氧/复氧导致的心肌炎症损伤，保护心肌细胞。

关键词： HLA-C*07:1179   new allele   PacBio sequencing  

摘要： HLA-C*07:1179 differs from HLA-C*07:02:01:01 by one nucleotide substitution at position 710 in exon 4.

关键词： 甲状腺功能减退症   循环细胞因子   孟德尔随机化研究   血清标志物   Hypothyroidism   Circulating Cytokines   Mendelian Randomization   Biomarkers  

摘要： 目的：探讨甲状腺功能减退症风险与循环细胞因子的因果关系，并确定用于识别甲减高危人群的生物标志物。方法：本研究采用双向孟德尔随机化(mendelian randomization, MR)分析，基于欧洲人群甲状腺功能减退症的全基因组关联(genome-wide association, GWAS)研究数据。选择41种循环细胞因子相关的遗传突变作为本实验的工具变量。为确保研究结果可靠，我们还增加了敏感性分析(基因多效性、异质性和leave-one-out测试)和反向MR评估。结果：结果显示甲状腺功能减退症风险与白细胞介素-8 (Interleukin-8 levels, IL-8)和白细胞介素-9水平(Interleukin-9 levels, IL-9)之间存在很强的因果关系。单核细胞趋化蛋白-1 (Monocyte chemoattractant protein-1 levels, MCP-1)和巨噬细胞炎症蛋白1b (Macrophage inflammatory protein 1b levels, MIP-1b)尽管显示出了很强的相关性，但没有通过敏感性测试。MR分析表明IL-8和IL-9是潜在的甲状腺功能减退症预测生物标志物。结论：本项孟德尔随机研究明确了特定循环细胞因子与甲状腺功能减退症风险之间存在因果关系，为识别甲状腺功能减退症高风险人群提供新的可靠预测生物标志物，并为探索免疫系统与甲状腺功能的复杂相关性提供生物学证据。

关键词： hematopoietic stem cell transplantation   HLA-identical siblings   graft versus host disease   HLA-DQB1*05  

摘要： Background/Objectives: Human leukocyte antigens (HLAs) are major determinants of successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). Their alleles are closely linked to outcomes, even in HLA-identical sibling donor (ISD) HSCT. This retrospective study analyzed the impact of HLA alleles on HLA-ISD HSCT outcomes in Omani patients. Methods: Data were collected for a heterogenous cohort of patients registered at the Sultan Qaboos University Hospital (SQUH), who underwent HLA-ISD HSCT from 2012 to 2022 (n = 153). HSCT outcomes, namely acute GVHD (aGVHD), chronic GVHD (cGVHD), chimerism status (complete or mixed) at 6 to 12 months after HSCT, neutrophil and platelet engraftment time, and patient five-year overall survival, were included. Low-resolution HLA-typing records were collected for five HLA loci: HLA-A, B, C, DRB1 and DQB1. GVHD and chimerism were analyzed by logistic regression analysis. Platelet and neutrophil engraftment times were assessed by Mann–Whitney tests. Patient overall survival was evaluated by the Kaplan–Meier model and Log-rank testing. At a 95% confidence interval, the p-value threshold was corrected using Bonferroni correction. Results: The incidence rates of aGVHD and cGVHD from all grades were 16% and 15%, respectively. Although no association between HLA alleles or any of the investigated outcomes was identified, survival curve analyses indicated a significant protective effect of HLA-DQB1*05 (p = 0.01). Patients carrying this allele had a better-estimated 5-year overall survival (90%) than did DQB1*05 negative patients (68%). Conclusions: This study suggests that HLA-DQB1*05 in the Omani population could have an impact on overall survival and might be a predictive biomarker. Further studies on a larger scale in other regional populations are needed to validate our findings and explore the underlying mechanism.

关键词： HLA-DQA1*03:80 novel allele   Illumina   next-generation sequencing  

摘要： The HLA-DQA1*03:80 allele contains a single nucleotide substitution in codon 134 (GGT to CGT).

关键词： mesenchymal stromal cells   human leukocyte antigens   interferon-γ   autoimmune disorders   advanced therapy medicinal products  

摘要： Mesenchymal stromal cells (MSCs) exert their immunoregulatory properties after licensing by inflammatory signaling cues, e.g., interferon (IFN)-γ. However, MSCs licensing by IFN-γ may result in increased expression of human leukocyte antigen (HLA) class II, which is related to rapid cell elimination, impairment of their immunosuppressive properties, and patient sensitization. The aim of this study was to evaluate the impact of IFN-γ on mediated immunoregulation and HLA class II expression. In this study, Wharton’s jelly (WJ) MSCs were isolated from human umbilical cords. Well-defined WJ-MSCs were submitted to IFN-γ exposure, and after 96 h, evaluation of biomolecule secretion and HLA class II expression was performed. Typing of HLA alleles using a next-generation sequencing (NGS) platform was performed. IFN-γ-primed WJ-MSCs secreted a high amount of immunoregulatory biomolecules, while elevated expression of HLA-DRB1 was observed. Analyses the NGS results showed the possibility of WJ-MSCs cluster formation based on their frequency of detected HLA alleles and immunoregulatory potential. Taking into consideration that IFN-γ-primed WJ-MSCs express HLA class II alleles, it is suggested that the HLA histocompatibility between allogeneic donor and recipient should be strongly considered to acquire the most beneficial outcome for the MSCs therapeutic strategy.

关键词： 3 mismatches in exon 3   HLA-B*08:339   NGS  

摘要： HLA-B*08:339 differs from HLA-B*08:25 by 3 mismatches in exon 3, which result in 3 non-synonymous mutations.

关键词： antiviral immunity   EBV   hCMV   HLA   KIR   NK cells   NKG2  

摘要： Natural killer (NK) cells are vital in the antiviral response regulated by inhibitory and activating receptors, including NKG2 and KIR families, which bind HLA-I. While the adaptive features of NK cells in response to human cytomegalovirus (hCMV) have been well described, their behavior during Epstein-Barr virus (EBV) infection and the influence of KIR-HLA combinations in healthy carriers of these viruses remains unclear. We performed high-resolution HLA genotyping, phenotypic profiling of NK cell subsets, and serological testing for hCMV and EBV-specific IgG in 85 healthy adult donors. hCMV-seropositive individuals exhibited significant expansions of NKG2C+ and HLA-DR+ NK cell subsets, with the proportion of NKG2C+ cells strongly correlating with hCMV-IgG titers. In contrast, EBV infection was associated with increased frequencies of terminally differentiated CD56dim, NKG2A-, CD57+ NK cells and elevated expression of inhibitory KIRs, but not NKG2C or HLA-DR. EBV-IgG titers correlated with CD57 and KIR2DS4 levels. Among KIR2DS4-expressing donors, carriage of at least one HLA-C2 allele was associated with elevated EBV-IgGs. The precise analysis of KIR2DL2/DL3, KIR2DS4, and KIR2DL1 revealed dependencies on EBV-IgG titers, with no associations with hCMV. These findings highlight the differential impacts of hCMV and EBV on NK cells and underscore the relevance of HLA-KIR landscapes in shaping antiviral immunity.

关键词： HLA-DPA1*02:01:01:37 novel allele   Illumina   next-generation sequencing  

摘要： The HLA-DPA1*02:01:01:37 allele differs from HLA-DPA1*02:01:01:19 by a single nucleotide substitution in intron 1.