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关键词： transplantation   chronic rejection   heme oxygenase-1   anti-HLA-1 antibodies   accommodation   endothelial cells   adhesion   monocyte transmigration  

摘要： The main risk factor for developing transplant vasculopathy (TV) after solid organ transplantation is de-novo production of donor-specific antibodies (DSAs) binding to endothelial cells (ECs) within the graft's vasculature. Diverse leukocyte populations recruited into the vessel wall via activated ECs contribute to vascular inflammation. Subsequent smooth muscle cell proliferation results in intima hyperplasia, the pathophysiological correlate of TV. We demonstrated that incubating aortic EC with anti-HLA-I antibodies led to increased monocyte adhesion to and transmigration across an EC monolayer. Both occurred in a CD62E-dependent fashion and were sensitive toward the anti-inflammatory enzyme heme oxygenase (HO)-1 modulation. Using a murine heterotopic aortic transplantation model, we demonstrated that anti-MHC I antibody-induced TV is ameliorated by pharmacologically induced HO-1 and the application of anti-CD62E antibodies results in a deceleration of developing TV. HO-1 modulation is a promising therapeutic approach to prevent leukocyte recruitment and subsequent intima hyperplasia in TV and thus precludes organ failure.

关键词： chimeric antigen receptor T cells   CAR-T   cytokine release syndrome   CRS   immune effector cell-associated neurotoxicity   ICANS   biomarkers   hypophosphatemia   modified endothelial stress activation index   m-EASIX  

摘要： Introduction: Cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome (ICANS) are both serious complications of CAR-T therapy associated with endothelial dysfunction, prompting prior use of a modified version of the endothelial activation and stress index (m-EASIX) to predict the occurrence of severe ICANS and CRS. Previous studies have linked both hypophosphatemia and elevated IL6 levels to CRS and ICANS. Our study aimed to enhance the early prediction of both syndromes by integrating phosphorous and IL-6 both together and separately into the m-EASIX score. Methods: Forty-two patients with non-Hodgkin's lymphoma presenting for CAR-T treatment were used to generate three variations in the m-EASIX score, assessing performance for the clinically actionable time points of day +0 through day +3. Results: The addition of phosphorous through the P-m-EASIX improved the predictive capabilities for the occurrence of ICANS, most notably on day +1 (AUC 89.6%;p = 0.0090, OR of 2.23;p = 0.0096) compared to the m-EASIX (AUC 80.8%;p = 0.0047, OR 1.72;p = 0.0046). The P-m-EASIX also showed enhanced predictive capabilities for the occurrence of CRS, with peak discriminatory function on day +3 (AUC 92.0%;p = <0.0001, OR 2.21;p = 0.0014). The addition of IL6 in the IL6-m-EASIX showed the highest discriminatory capacity for the prediction of CRS progression to grade >= 2 with peak function on day +3 (AUC 89.7%;p = 0.0040, OR 1.57;p = 0.031). Conclusions: Incorporating phosphorus levels into the m-EASIX score offered a cost-effective and straightforward method to improve the prediction of CAR-T toxicities. Larger-scale studies assessing the effectiveness of including phosphorus and IL-6 in the m-EASIX score to mitigate complications associated with CAR-T therapy are warranted.

关键词： dengue infection   endogenous retroviruses   severity progression of dengue   vascular leakage   HERV   RNA-seq -RNA sequencing   pro-inflammatory genes   immune modulation  

摘要： Introduction Human Endogenous Retroviruses (HERVs), which can be activated by viral infections, have complex roles in gene regulation and immune modulation. However, their contribution to disease progression is not yet fully understood. Dengue fever ranges from mild symptoms to severe cases characterized by plasma leakage and immune dysregulation, providing a relevant context to investigate these *** This study comes up with a comprehensive analysis of differentially expressed HERVs (DE-HERVs), protein-coding genes (DEGs), and regulatory elements such as microRNAs (DE-miRNA) and non-LTR retroviruses (DE-LINEs and DE-SINEs) derived from the transcriptomes of Brazilian dengue patients across different disease *** The results show that DE-HERVs are associated with key genes identified in severe dengue cases, including ARG1, SLC15A2, COL3A1, SVEP1, CH25H, CST7, CXCR1, IL18RAP, SORL1, and TACR1, suggesting their role in immune modulation and endothelial permeability. Specifically, the upregulation of CXCR1 and IL18RAP genes in patients who progressed to severe dengue correlates with a complex regulatory network involving down-regulated microRNAs (miRNAs) and non-LTR retroviruses, emphasizing their relevance to inflammation and vascular permeability. MicroRNAs and non-LTR retroviruses were found to regulate these genes differently across dengue stages, with non-LTR elements appearing predominantly in non-severe cases and miRNA expression profiles varying across the comparison *** These findings improve our understanding of the molecular mechanisms underlying dengue progression and suggest that HERV-related regulatory networks may influence viral infections. Further research is required to clarify the specific roles of HERVs in dengue pathogenesis.

关键词： 唾液腺炎   碘放射性同位素   超敏反应   腮腺   下颌下腺  

摘要： 目的：探索临床上常见的几类不同病因导致的慢性唾液腺炎的所占比例，并分析其临床和影像学特点。方法：回顾性分析2021年1月至2023年8月就诊于北京大学口腔医院并行唾液腺内镜治疗的各类慢性唾液腺炎患者的临床及影像资料，除外干燥综合征伴感染、IgG4相关唾液腺炎、结石病伴感染等。根据现有研究结果和资料，初步将唾液腺炎分为131I相关唾液腺炎、过敏相关唾液腺炎、成人复发性腮腺炎、腮腺良性肥大伴管炎、原发性导管狭窄性唾液腺炎（指未发现目前已知的可能病因，并存在导管狭窄的慢性唾液腺炎），统计分析各类慢性唾液腺炎的占比和主要临床、影像学特点。结果：共纳入544例患者，男性192例、女性352例，平均年龄（47.44±13.52）岁（14～83岁）。其中，原发性导管狭窄性唾液腺炎最多，占71.7%（390例）；过敏相关唾液腺炎次之，占12.5%（68例）；131I相关唾液腺炎占6.4%（35例），成人复发性腮腺炎占4.8%（26例），腮腺良性肥大伴管炎占4.6%（25例）。544例患者共1 120侧腺体受累，包括腮腺880侧（78.6%）及下颌下腺240侧（21.4%）。这5类唾液腺炎在性别、年龄、受累腺体类别、受累腺体数目及病程上差异均存在统计学意义（P<0.05）,131I相关唾液腺炎患者的女性占比最高（男:女=1:4.83），成人复发性腮腺炎患者的平均年龄最小【（32.50±8.60）岁】，131I相关唾液腺炎和过敏相关唾液腺炎的受累腺体数目相对较多。从造影表现看，131I相关唾液腺炎中23.2%的受累腺体发生导管闭锁，过敏相关唾液腺炎中46.5%的受累腺体分支导管呈“雪花样”扩张表现，成人复发性腮腺炎中80.4%的受累腺体可见末梢导管“点球状扩张”，腮腺良性肥大伴管炎的受累腺体分支导管呈丛簇状表现者占71.4%，原发性导管狭窄性唾液腺炎的造影表现以主导管（和分支导管）狭窄和/或扩张为主。结论：原发性导管狭窄性唾液腺炎、131I相关唾液腺炎、过敏相关唾液腺炎、成人复发性腮腺炎、腮腺良性肥大伴管炎是临床上常见的五类慢性唾液腺炎，其中原发性导管狭窄性唾液腺炎占比最大。明确各类慢性唾液腺炎的致病原因、临床及影像学特征，有利于临床医师制定个性化治疗方案，改善治疗效果。

关键词： 非洲猪瘟病毒   pH124R蛋白   原核表达   多克隆抗体  

摘要： 首先，通过PCR扩增和同源重组技术构建了pET-28a-H124R重组原核表达质粒。经IPTG诱导，pH124R蛋白在大肠杆菌中高效表达，并通过镍柱亲和层析法纯化获得重组蛋白。随后，用pH124R重组蛋白免疫豚鼠，制备了特异性多克隆抗体。通过SDS-PAGE、Western-blot和间接免疫荧光试验（IFA）对其进行检测，结果表明该抗体能够特异性识别ASFV感染细胞中表达的内源pH124R蛋白，且该蛋白主要定位于细胞质病毒工厂区域。本研究成功实现了ASFV pH124R蛋白的原核表达，并制备了可用于Western-blot和IFA试验的特异性多克隆抗体，为深入研究pH124R蛋白的生物学功能提供了重要生物学材料。

关键词： Soluble receptor   Il10   Il4   Amyloid   Tau   Therapy   Circadian rhythm  

摘要： Multiple lines of evidence indicate that immune signaling can impact the pathological progression in Alzheimer's disease (AD), including amyloid deposition, tau aggregation, synaptic pathology and neurodegenerative trajectory. In earlier studies, we reported that intracerebral expression of the anti-inflammatory cytokines, Interleukin-10 (Il10) and Interleukin-4 (Il4), increased amyloid beta (A beta) burden in TgCRND8 mice, a preclinical model of AD-type amyloidosis. As both Interleukin-10 receptor (IL10R) and Interleukin-4 receptor (IL4R) are upregulated in an age-progressive manner in rodent models of AD and in specific regions of human AD brains, we hypothesized that a decoy receptor strategy specifically targeting Il10 and Il4 signaling could have a disease-modifying effect. We derivatized the ectodomains of mouse Il10R (sIl10R) and mouse Il4R (sIl4R) into corresponding recombinant solubilized receptor forms and delivered these intracranially into neonatal TgCRND8 mice or hippocampally into adult TgCRND8 mice with pre-existing A beta deposits. AAV-mediated expression of sIl10R and sIl4R robustly attenuated A beta burden in TgCRND8 mice when expressed neonatally while in the hippocampus injection cohort, AAV-sIl4R, but not sIl10R, reduced A beta burden. sIl10R and sIl4R had opposing effects on microglial and astrocyte proliferation, with sIl10R generally reducing gliosis. RNAseq analysis showed that sIl10R likely acts as a microglial immune checkpoint inhibitor while both sIl10R and sIl4R expression show unexpected impacts on genes related to circadian rhythm. Notably, neither Il10 nor sIl10R expression altered tau pathology in two tau transgenic models, despite robust expression and impacts on glial proliferation. Together, these data reveal that decoy receptor mediated targeting of physiological Il10 or Il4 signaling can beneficially impact amyloid deposition and thus represent novel immunomodulatory approaches for AD therapy.

摘要： Escherichia coli K1 (E. coli K1) meningitis early occurs in the gastrointestinal and causes severe damage to the central nervous system, including lifelong neurological complications in survivors. However, the cellular mechanism by which E. coli K1 may cause neuropathies is not well understood due to the lack of relevant human multi-organ models for studying multifaceted systemic inflammation across the gut-brain axis. Here, we reconstruct a multicellular model of the human gut-brain axis to identify the neuropathogenic mechanism driven by E. coli K1-colibactin meningitis. We observed that E. coli K1-genotoxic colibactin induced intestinal and peripheral interleukin 6, causing the blood-brain barrier injury and endothelial inflammation via the p38/p65 pathways. Serpin-E1 from the damaged cerebral endothelia induces reactive astrocytes to release IFN-gamma, which reduces microglial phagocytosis of E. coli K1 and exacerbates detrimental neuroinflammation via NLRP3/IL-18 axis. Microglial IL-18 elevates neuronal reactive oxidative stress that worsens DNA double-strand breaks in E. coli K1-infected neurons, leading to H3K4 trimethylation and phosphorylation of alpha-synuclein. Our findings suggest therapeutic strategies for post-bacterial meningitis treatment to potentially prevent the initiation of synucleinopathy.

关键词： ankylosing spondylitis   acute anterior uveitis   HLA-B27   single cell CITE sequencing   immunophenotype  

摘要： Ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis (r-axSpA), is an immune-mediated inflammatory disorder frequently associated with acute anterior uveitis (AAU). Both conditions share a strong association with the genetic risk factor, human leukocyte antigen (HLA)-B27. However, the immunophenotype underlying HLA-B27-associated AS and/or AAU pathophysiology remains known. Using cellular indexing of transcriptomes and epitopes (CITE-Seq) in a well-characterized cohort of 25 subjects-including AS (HLA-B27pos), AS+AAU (HLA-B27pos), AAU (HLA-B27pos), HCs (HLA-B27pos), and HCs (HLA-B27neg);N = 5/group-we identified transcriptomic differences at the single-cell level, along with differentially expressed cell surface markers. Our study elucidates both shared and distinct immune alterations linked to HLA-B27 and disease. Furthermore, we employed sparse decomposition of arrays (SDA) analysis, an unsupervised machine learning method, to examine the high-dimensional transcriptional landscape of our data and identify complex and nonlinear relationships. Our study identified HLA-B27- and disease-specific transcriptomic differences in AS and AAU. The immune profiles of AS+AAU closely resembled those of AS, suggesting AS plays a dominant role in immune dysregulation. SDA analysis further revealed dysregulated B-cell maturation and activation in AS subjects, whereas AAU subjects exhibited an enrichment of cytotoxic effector function in T and NK cells. However, both AS and AAU exhibited myeloid cell activation, a key process in initiating and sustaining inflammation. Additionally, both AS and AAU subjects showed a dampening in homeostatic function, i.e., the balance between identifying and actively eliminating foreign pathogens while preventing an immune response against self-antigens, suggesting that inflammation may arise from immune dysregulation. In conclusion, our results highlight overlapping myeloid effector involvement, along with distinct immuno

关键词： Sepsis   Acute respiratory distress syndrome   Immune microenvironment   Immune infiltration  

摘要： The onset of sepsis frequently coincides with acute respiratory distress syndrome (ARDS), which constitutes a significant contributor to severe acid-base disturbances in septic patients. In the pathogenesis of sepsis, it conducts a crucial role. lysosomal metabolic disorders and immune imbalance conduct a pivotal role. Despite extensive research into the alterations in immune status during sepsis, few studies have been reported to thoroughly examine the association between lysosomes and sepsis. As a result, this study is predominantly Intended to delve into the link between lysosome-related genes and alterations in the lysosome in the immune microenvironment from the standpoint of bioinformatics in sepsis. The Registration Number was ChiCTR1900021261. Registration Date is 2019/02/*** Sepsis data source: Sepsis data was collected from previous clinical data and sequencing results (Originated from BGI Shenzhen Co., Ltd.) and the GO database was utilized for data collection of lysosome-related genes. Differential expression genes (DEGs) were screened on clinical sequencing data by employing IDEP 0.93 software subsequent to quality control. Afterwards, enrichment analysis was conducted by adopting Gene Set Enrichment Analysis (GSEA) and Weighted Gene Co expression Network Analysis (WGCNA), followed by cross referencing of lysosomal genes to identify DEGs associated with lysosomes. GO and KEGG pathway analysis wereperformed subsequently. The genes obtained from PLSGs and WGCNA by Creating a PPI network entails the following steps: the points were intersected at first. Afterwards, CytoHubba and MCODE analysis were performed by utilizing cytoscape software. Next, the intersection was taken to confirm Hub gene sequences, and subsequently the central DEGs tightly associated with existing CTD scores. Notwithstanding the fact that the causes of sepsis are multifaceted, ARDS can often trigger the development of sepsis in numerous cases. Simultaneously, with an aim to pred

关键词： 解表清里方   甲型流感病毒   流行性感冒   Toll样受体7(TLR7)/丝裂原活化蛋白激酶(MAPK)/核转录因子-κB(NF-κB)信号通路   细胞因子  

摘要： 目的：探讨解表清里方对甲型流感病毒（IAV）感染所致肺炎的药效机制。方法：将132只Bal/c小鼠随机分为空白（NC）组、模型（IAV）组、奥司他韦（OSV）组(37.5 mg·kg-1)、高、中、低剂量解表清里方（H、M、L-JQD）组(6.05、3.02、1.51g·kg-1)。NC组给予生理盐水滴鼻，其他各组在鼻内接种A/Brisbane/02/2018（H1N1）[pdm09-like virus （H1N1）]构建流感病毒感染的动物模型。造模2 h后，NC组和IAV组给予生理盐水灌胃，其他各组给予对应药物灌胃，7 d。给药期间每日记录小鼠体质量、生存状态、死亡数量。第3、7天测量小鼠肺指数；苏木素-伊红（HE）染色观察肺组织病理形态学变化；使用实时荧光定量聚合酶链式反应（Real-time PCR）法检测肺组织中病毒载量（IAV-M）、Toll样受体7（TLR7）、p38丝裂原活化蛋白激酶（p38 MAPK）、核转录因子-κB（NF-κB）的mRNA表达；使用蛋白免疫印迹法（Western blot）检测肺组织中p38 MAPK、NF-κB蛋白表达水平；使用酶联免疫吸附测定法（ELISA）检测血清中白细胞介素-2（IL）-2、IL-6、肿瘤坏死因子（TNF）-α含量。结果：与NC组比较，IAV组小鼠生存质量下降，生存天数减少（P<0.01），肺部充血、炎性细胞浸润，肺指数升高（P<0.01），病毒载量升高（P<0.01），TLR7、p38 MAPK、NF-κB升高（P<0.05，P<0.01），IL-2降低（P<0.01），IL-6、TNF-α升高（P<0.01）。与IAV组比较，H-JQD组小鼠生存天数延长（P<0.05）；JQD三组小鼠肺组织病理改变减轻，肺指数下降（P<0.01）；M、H-JQD组小鼠肺组织病毒载量减少（P<0.01）。与IAV组比较，H-JQD组小鼠TLR7、p38 MAPK、NF-κB mRNA表达降低（P<0.05，P<0.01），p38 MAPK、NF-κB蛋白表达水平减少（P<0.01），血清中IL-2含量增加（P<0.01），IL-6、TNF-α含量减少（P<0.05，P<0.01）；M-JQD组小鼠肺组织NF-κB mRNA表达降低（P<0.01），p38 MAPK蛋白表达水平减少（P<0.05），血清中IL-2含量增加（P<0.01），TNF-α含量减少（P<0.01）。结论：M、H-JQD剂量依赖性地下调TLR7/MAPK/NF-κB信号通路，增加IL-2，减少IL-6、TNF-α细胞因子的过度分泌，从而改善IAV感染所致的肺炎。