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摘要： During double umbilical cord blood transplant (DUCBT), the winning unit (WU) rejects the losing unit (LU) because of WU T cells directed against the LU mismatched HLA. This immune response might protect against relapse, especially when the patient and LU (PT-LU) share the same mismatch with the WU. To validate this hypothesis, a retrospective Eurocord study, conducted on 383 DUCBTs, focused on posttransplant relapse and HLA mismatches between PT-LU and the WU. A PT-LU HLA-A mismatch shared with the WU was associated with a lower 7-year relapse incidence (16% vs 28%;P = .048). In addition, multiple PT-LU shared HLA mismatches were also associated with a lower relapse risk (7% vs 29%;P = .003). In DUCBT with >= 2 HLA mismatches between patient and WU, the number of HLA mismatches between those did not significantly affect relapse incidence, whereas multiple PT-LU shared HLA mismatches remained associated with a lower relapse risk (7% vs 29%;P = .0038). Finally, considering patients who did not develop either grade 2 to 4 acute graft-versus-host disease or chronic graft-versus-host disease, a PT-LU shared HLA-A mismatch as well as multiple PT-LU HLA mismatches shared with the WU remained associated with a significantly lower 7-year relapse incidence. In multivariate adjusted analyses multiple PT-LU shared HLA mismatches remained associated with a significantly reduced 7-year posttransplant relapse risk. Our analysis indicates that, during DUCBT, PT-LU shared HLA mismatches prime an immune response of the WU against leukemia, reducing the long-term risk of posttransplant relapse, and that DCBT has particular utility in those with high-risk leukemia.

关键词： Colorectal Cancer   Non-Small Cell Lung Cancer   Human leukocyte antigen - HLA   Immunotherapy   Adoptive cell therapy - ACT  

摘要： T-cell receptors (TCRs) recognize antigens derived from fragments of somatically expressed proteins that are degraded by the proteasome and presented by specific human leukocyte antigen (HLA) molecules. Recent therapeutic advances using the TCR as a tumor-targeting moiety have focused attention on HLA loss of heterozygosity (LOH) as a potential resistance mechanism. Allele-specific LOH, rather than allele-agnostic, is particularly pertinent, but rarely evaluated. Using a real-world dataset comprising 78,418 cases, we demonstrate that allele-specific LOH occurs at a relatively low frequency (<10%) across all patients with cancer. We observed a modest increase in allele-specific HLA LOH in cancers harboring associated neoantigen driver mutations (eg, KRAS or TP53 mutations), but the overall frequency remained consistently low. Furthermore, using an orthogonal dataset, we integrated clinical outcomes with HLA LOH and identified distinct impacts on overall survival in colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) cohorts. For instance, A*02:01-specific LOH was linked to worse survival in CRC (HR 0.5355, 95% CI 0.2991 to 0.9589, p=0.0094) but showed a trend toward improved survival in NSCLC (HR 1.249, 95% CI 0.7778 to 2.005). These findings underscore the relevance of allele-specific HLA LOH assessments and reveal nuanced differences in its clinical implications, which should be accounted for in the optimization of TCR-based immunotherapies.

关键词： italic>Yersinia   infectious disease   tumor necrosis factor   gastrointestinal infection   infection dynamics   bacterial infection   innate immunity  

摘要： Enteroinvasive bacterial pathogens are responsible for an enormous worldwide disease burden that critically affects the young and immunocompromised. Yersinia pseudotuberculosis is a gram-negative enteric pathogen closely related to the plague agent Y. pestis that colonizes intestinal tissues, induces the formation of pyogranulomas along the intestinal tract, and disseminates to systemic organs following oral infection of experimental rodents. Prior studies proposed that systemic tissues were colonized by a pool of intestinal replicating bacteria distinct from populations within Peyer's patches and mesenteric lymph nodes. Whether bacteria within intestinal pyogranulomas serve as the source for systemic dissemination and the relationship between bacterial populations within different tissue sites is poorly defined. Moreover, the host factors that regulate Yersinia colonization and dissemination are not well understood. Here, we demonstrate using sequence tag-based analysis of microbial populations in R (STAMPR) that remarkably small founder populations independently colonize intestinal and systemic tissues. Notably, intestinal pyogranulomas contain clonal populations of bacteria that are restricted and do not spread to other tissues. However, Yersinia populations are shared among systemic organs and the blood, suggesting that systemic dissemination occurs via hematogenous spread. Finally, we demonstrate that TNF signaling is a key contributor to the bottlenecks limiting both initial colonization and subsequent dissemination of orally acquired bacterial populations. Altogether, this study reveals previously undescribed aspects of infection dynamics of enteric bacterial *** of bacteria following intestinal infection can lead to severe disease, including sepsis, organ damage, and death. However, the intestinal bacterial population dynamics governing the colonization of mucosal and systemic tissues and the intestinal sites that seed systemic

关键词： obesity   adipose tissue   Th2 response   IL-4   IL-13  

摘要： The Th2 immune response, associated with allergic diseases and helminth infections, has emerged as a significant modulator of metabolic processes in adipose and liver tissues. Th2 cytokines, such as IL-4, IL-5, and IL-13, regulate energy metabolism, insulin resistance, and obesity-related issues. IL-4 and IL-13 play significant roles, while IL-5 mainly recruits eosinophils in visceral fat. IL-4 influences lipid metabolism via STAT6, promoting adipogenesis, lipolysis, and reducing leptin levels, thereby improving insulin resistance or inducing white adipose browning in the absence of leptin. IL-13 affects glucose metabolism by lowering gluconeogenesis and enhancing glucose control and increases energy expenditure in muscles during exercise via STAT3. Emerging therapies include recombinant cytokines, exosomes, and monoclonal antibodies targeting IL-4/IL-13 or IL-5, which are mostly approved for the treatment of allergic diseases. Their use in metabolic disorders is largely unexplored. Overall, Th2 cytokines are promising targets for obesity and metabolic diseases but require dedicated trials to assess benefits and risks.

关键词： 鸡   早幼粒细胞白血病蛋白   单克隆抗体   定位   表达分布  

摘要： 研究旨在研制抗鸡源早幼粒细胞白血病蛋白（PML）的单克隆抗体。试验采用PCR和同源重组技术构建鸡PML基因的1 228～1 566 nt原核表达质粒，命名为pGEX-6p-1-PML-P2。使用IPTG诱导表达后，以纯化成功的GST-PML-P2蛋白免疫小鼠，将小鼠脾细胞与骨髓瘤细胞SP2/0融合，通过间接免疫荧光（IFA）方法筛选出阳性细胞克隆；用激光共聚焦、Western blot及免疫沉淀（IP）验证单克隆抗体的特性。结果显示：成功获得3株能够分泌抗鸡PML单克隆抗体的杂交瘤细胞株，命名为4C2、3F4和4G3;3株单克隆抗体的亚类均为IgG1，其腹水的IFA效价分别为1∶6 400(4C2)、1∶12 800(3F4)和1∶25 600(4G3)；单克隆抗体4C2可特异性检测禽源细胞（HD11、MSB-1、LMH和DF-1）及非禽源细胞（MDCK、MA104和293T）中的内源性PML蛋白，激光共聚焦可观察到DF-1细胞内源性PML蛋白在细胞核内呈点状分布；3株单克隆抗体均能有效免疫沉淀外源高表达的鸡PML蛋白且单克隆抗体4C2能有效免疫沉淀DF-1细胞内源性的PML蛋白，确定PML在鸡的心脏、肝脏、脾脏、肺脏、肾脏、胸腺及法氏囊组织中广泛表达。研究表明，成功制备的3株抗鸡PML单克隆抗体可以有效检测不同细胞系及鸡组织中的PML蛋白并免疫沉淀细胞中内源及外源表达的PML蛋白，为深入探究鸡PML蛋白的功能及其在禽类疾病防控中的应用提供了不可或缺的工具。

关键词： Cancer immunotherapy   Coagulation   Immunology   Oncology   Platelets   Vascular biology  

摘要： Malignancies increase the risk for thrombosis and metastasis dependent on complex interactions of innate immune cells, platelets, and the coagulation system. Immunosuppressive functions of platelets and macrophage-derived coagulation factors in the tumor microenvironment (TME) drive tumor growth. Here, we show that patients with malignancies and tumor-bearing mice have increased levels of coagulation factor (F) X-expressing circulating monocytes engaged in platelet aggregate formation. This interaction and resulting thrombin generation on platelets interferes with monocyte differentiation and antigen uptake of antigen-presenting cells (APCs). Myeloid cell-specific deletion of FX or abrogated FXa signaling via protease activated receptor 2 (PAR2) averts the suppressive activity of platelets on tumor cell debris uptake and promotes the immune stimulatory activity of APCs in the TME. Myeloid cell FXa-PAR2 signaling deficiency specifically enhances activation of the cGAS-STING-IFN-I pathway with a resulting expansion of antigen oral anticoagulants expands T cell priming-competent immune cells in the TME and synergizes with the reactivation of exhausted CD8+ T cells by immune checkpoint inhibitors for improved antitumor responses. These data provide mechanistic insights into the emerging clinical evidence demonstrating the translational potential of FXa inhibition to synergize with immunotherapy.

关键词： 人内源性逆转录病毒   瞬时表达   单克隆抗体   结合活性   阻断活性   抗体亲和力   多发性硬化   1型糖尿病  

摘要： 目的 瞬时表达人内源性逆转录病毒W家族包膜蛋白（human endogenous retroviruses W family Env protein， HERV-W Env），将其作为免疫原制备单克隆抗体（monoclonal antibody， mAbs）并对mAbs进行鉴定研究。方法 采用构建成功的pcDNA3.4（+）-HERV-W Env-His重组质粒（简称HERV-W Env重组质粒）瞬时转染Expi 293F细胞进行蛋白表达；采用二喹啉甲酸（bicinchoninic acid assay， BCA）法、SDS-PAGE及Western blot检测蛋白浓度、相对分子质量、纯度及特异性。免疫BALB/c小鼠并通过杂交瘤技术制备mAbs，采用BCA、SDS-PAGE、Western blot、ELISA及表面等离子共振（surface plasmon resonance， SPR）法分别检测mAbs的浓度、纯度、特异性、亚型、结合活性、阻断活性及亲和力。结果 表达了浓度为1.2 mg/mL的HERV-W Env蛋白，SDS-PAGE结果显示其完整蛋白的相对分子质量约为55 000，去糖基化后相对分子质量与理论值36 300一致，蛋白纯度为90%；Western blot结果显示其可被特异性抗体识别。免疫BALB/c小鼠血清效价均达到1×105；筛选得到6株mAbs，浓度为0.63～10.00 mg/mL；抗体亚型均为IgG1 κ亚型；SDS-PAGE结果显示6株mAbs的抗体结构以及重轻链完整，纯度均＞90%；Western blot结果显示6株mAbs均可与HERV-W Env蛋白氨基酸表位结合；6株mAbs结合活性为40.79～140.40 pmol/L，阻断活性为1.86～13.93 nmol/L；选结合活性及阻断活性较好的mAb 7H8、4A6、2C1检测亲和力，亲和力常数依次为1.468×10-10、5.227 ×10-10、6.799 ×10-10mol/L。结论 以HERV-W Env蛋白为免疫原制备的6株mAbs，均展现出良好的结合活性、阻断活性及亲和力，这6株mAbs可作为针对多发性硬化（multiple sclerosis， MS）、1型糖尿病（type 1 diabetes， T1D）等疾病的创新抗体药物候选抗体株进行下一步的研究。

关键词： inflammation   cell-junction dynamics   actin dynamics   JAIL   stress fibers   contractility   VE-cadherin dynamics   shear stress  

摘要： Inflammatory endothelial phenotypes describe distinct cellular patterns essential for controlling transendothelial migration of leukocytes (TEM). While TNF-alpha-induced CAM expression mediates leukocyte interaction, the role of a potential inflammatory morphological phenotype (IMP) - characterized by barrier-function decrease and shape-change in TEM - remains unclear. This study identifies the TNF-alpha-induced IMP as indispensable for neutrophil TEM, while regulating barrier-function. The TNF-alpha-induced IMP progresses through two states: an intermediate state that transiently enhances barrier function via MLC-dephosphorylation, junctional actin recruitment and VE-cadherin linearization, protecting the monolayer from collapse;while the subsequent development of the IMP requires MLC rephosphorylation, junctional actin disassembly, stress fiber formation and Arp2/3-mediated membrane protrusions causing shape-change. This in turn dilutes junctional VE-cadherin, forming intercellular gaps for neutrophil TEM, while inducing junction-associated intermittent lamellipodia (JAIL) to locally restore VE-cadherin adhesion, appearing as gap/JAIL cycles driving junctional dynamics. VE-cadherin overexpression blocks TNF-alpha-induced IMP and gap/JAIL cycling, reducing TEM by similar to 80% without altering CAM expression. These findings highlight gap/JAIL cycling and MLC phosphorylation as key IMP regulators and potential therapeutic targets for inflammatory diseases.

关键词： inflammasome   NLRP1   gestational malaria   Plasmodium falciparum   Plasmodium vivax   trophoblasts  

摘要： We hypothesized that variants in inflammasome-related genes could influence susceptibility to gestational malaria (GM). To test this, we conducted an association study in a cohort of pregnant women from a malaria-endemic region in northern Brazil, assessing whether specific functional single nucleotide variants (SNVs) in inflammasome genes affect (1) the response to Plasmodium infection and (2) the development of placental malaria. Our findings revealed that the NLRP1 ***1154Val variant was associated with a protective effect against Plasmodium infection. Moreover, IL1B SNVs appeared more prevalent in severe cases. Additionally, multivariate analyses incorporating placental blood cytokines, growth factors, and immunohistochemical features revealed that the NLRP1 ***1154Val variant correlated with a healthier placental state, highlighting a potential protective role of the NLRP1 inflammasome in GM. For the first time, we showed that infected red blood cells induce NLRP1- and caspase-1-dependent pyroptosis in BeWo trophoblast cells, identifying a novel inflammasome pathway involved in GM pathogenesis. Our study identifies a genetic variant underlying NLRP1 contribution to GM and suggests that NLRP1 may be an under-explored inflammasome receptor in malaria and infected erythrocytes' sensing. (c) 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

关键词： 气道炎症   急性肺损伤   慢性阻塞性肺疾病   DnaK   交叉反应   自身免疫   补体   补体依赖的细胞毒性  

摘要： 目的 探究脂多糖（lipopolysaccharide， LPS）诱导的急性肺损伤模型和慢性阻塞性肺疾病模型（慢阻肺病，chronic obstructive pulmonary disease， COPD）中，抗细菌源性DnaK蛋白特异性IgG抗体通过“交叉识别”体内同源蛋白所介导的气道炎症的发生机制。方法 通过ELISA检测COPD模型小鼠血清中DnaK蛋白特异性IgG抗体水平，制备抗肺炎链球菌源性DnaK蛋白多克隆抗体，通过免疫荧光染色检测人肺泡上皮细胞A549细胞和小鼠肺上皮细胞MLE-12细胞中DnaK蛋白的表达和分布情况，通过免疫组化染色检测急性肺损伤模型和COPD模型小鼠肺组织区域DnaK蛋白免疫反应性；通过LPS叠加DnaK蛋白特异性IgG抗体构建联合刺激模型，检测支气管肺泡灌洗液（bronchoalveolar lavage fluid， BALF）总细胞计数判断气道炎症程度，苏木素-伊红（hematoxylin and eosin， HE）染色观察肺部炎症细胞浸润情况，免疫组化染色观察气道上皮细胞紧密连接蛋白（ZO-1、Claudin-1、Occludin）免疫反应性，ELISA检测血清和肺组织匀浆中补体活化产物C5b-9表达水平。结果 慢阻肺病模型小鼠血清中DnaK蛋白的特异性IgG抗体水平升高（t =11.71，P< 0.000 1）；抗肺炎链球菌源性DnaK蛋白特异性抗体可以交叉识别小鼠和人的肺上皮细胞胞浆中表达的DnaK蛋白，且在急性肺损伤和慢阻肺病模型鼠中均可观察到肺组织区域的DnaK蛋白免疫反应性升高（P均＜0.001）；LPS叠加DnaK蛋白特异性抗体会导致肺部炎症加重（P＜0.000 1），气道和血管周围炎性细胞浸润增多（P＜0.000 1），气道上皮细胞紧密连接蛋白ZO-1、Claudin-1和Occludin免疫反应性大幅下降（P均＜0.001），血清和肺组织匀浆中C5b-9的表达水平升高（P均＜0.001）。结论 抗细菌源性DnaK蛋白特异性抗体可以通过“交叉识别”急慢性炎症期间机体暴露的同源蛋白，激活补体并启动补体依赖的细胞毒性（complement dependent cytotoxicity， CDC），介导针对机体自身的免疫病理损伤，最终导致气道慢性炎症的发生、发展。