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关键词： IL-28B   HTLV-1   HAM/TSP   HTLV-1 related diseases  

摘要： This research addresses IL-28B gene polymorphisms (rs12979860 and rs8099917) to determine their association with HTLV-1-related diseases;it aims to compare genotypic frequencies to identify predisposition or protection, considering population, disease, and controls. Given HTLV-1's impact on immunity, this study seeks biomarkers for early diagnosis and intervention. A systematic search met inclusion criteria, such as open access bibliographic and experimental studies published in English between 2010 and 2024, and genetic factors linked to susceptibility to pathologies. Regarding exclusion criteria, bibliographic or experimental studies in organisms other than humans, unofficial sources, non-indexed journals, and scientific articles in languages other than English were ruled out. Statistical data analyses were assessed using meta-analysis, including forest plot and Q test of heterogeneity based on the I2 statistics. The analyzed data indicate associations between genotypes, such as CT, GG, CC, and TT of the rs12979890 and rs8099917 polymorphisms and the predisposition to various diseases, such as HCV, arthropathy, HAM/TSP, cytomegalovirus and Crimean-Congo hemorrhagic fever associated with HTLV-1;however, the observed inconsistencies, such as high heterogeneity, and deficiency of related information limit the consolidation of the findings. Further research is needed to clarify IL-28B genotype interactions and disease susceptibility in HTLV-1 infections.

摘要： Intestinal epithelial-derived IL-18 is critical for homeostatic intestinal barrier function and is secreted through Gasdermin D (GSDMD) pores. Inflammasome activation is a prerequisite for both IL-18 maturation and GSDMD pore formation. However, GSDMD pores also cause pyroptotic cell death, which could be detrimental to the intestinal epithelial barrier. How epithelial cells balance the need to secrete IL-18 and to maintain barrier integrity remains poorly understood. In human intestinal epithelial cell lines and in primary human epithelial intestinal organoids, but not in immune cells, GSDMD plasma membrane pore formation by LPS electroporation and by gram-negative bacterial infection induced a non-conventional p37 caspase-4 fragment that was associated with reduced levels of mature IL-18. By contrast, limiting GSDMD plasma membrane pores pharmacologically and via point-mutagenesis prevented caspase-4 cleavage and increased IL-18 production, suggesting that p37 caspase-4 cleavage may regulate IL-18 maturation in the intestinal epithelium. In support, co-expression of caspase-4 cleavage mutants and IL-18 in HEK293T cells revealed that non-cleavable caspase-4 produced more mature IL-18 than cleaved caspase-4. Overall, these studies suggest that epithelial inflammasomes encode feedback pathways that control the balance between cytokine secretion and cell death. This may be an important mechanism to ensure homeostatic IL-18 production in the intestinal epithelium.

关键词： COVID-19   SARS-CoV-2   NL63   ACE2   IFN-beta   platform technology   fusion protein   type I interferon   flow cytometry   drug discovery   antivirals   emerging/re-emerging RNA viral pathogens   immunomodulators  

摘要： The COVID-19 pandemic highlighted the need for new therapeutic strategies to counter emerging pathogenic viruses. Herein, we introduce a novel fusion protein platform that enables antiviral targeting of distinct viral species based on host receptor specificity. Proof-of-concept studies focused on the human coronavirus NL63, which shares specificity for the ACE2 host receptor with the pandemic SARS-CoV and SARS-CoV-2 species. This antiviral fusion protein combines IFN-beta with the soluble extracellular domain of ACE2 (IFN beta-ACE2). Both domains retained predicted bioactivities in that the IFN-beta domain exhibited potent antiproliferative activity and the ACE2 domain exhibited full binding to the transmembrane SARS-CoV-2 Spike protein. In virus-washed (virus-targeted) and non-washed in vitro infection systems, we showed that the pool of IFN beta-ACE2 targeted to the virion surface had superior antiviral activity against NL63 compared to soluble ACE2, IFN-beta, or the unlinked combination of ACE2 and IFN-beta. The pool of IFN beta-ACE2 on the virion surface exhibited robust antiviral efficacy based on the preemptive targeting of antiviral IFN-beta activity to the proximal site of viral infection. In conclusion, virus-targeted IFN-beta places interferon optimally and antecedent to viral infection to constitute a new antiviral strategy.

关键词： 湿地病毒   Gc抗原   单克隆抗体  

摘要： 目的 抗体是治疗病毒感染的重要手段之一，本研究针对正内罗病毒属湿地病毒表面Gc糖蛋白筛选制备特异性单克隆中和抗体。方法 通过构建湿地病毒表面糖蛋白Gc重组表达载体，Gc抗原免疫小鼠后提取脾脏总RNA，构建鼠源Fab（Antigenbindingfragments，Fab）抗体库。通过噬菌体展示技术筛选针对抗原Gc的Fab抗体。筛选成功后，对筛选出的Fab抗体选择人源hIgG1重链亚型进行抗体全长构建，并通过双质粒转染系统在ExpiCHO细胞中进行表达。通过酶联免疫吸附试验检测抗体与Gc抗原的结合活性，并利用免疫空斑试验对抗体的有效性进行初步评估。结果 构建了库容量为3.33×108cfu的Fab噬菌体抗体库，筛选出两株抗体A1、A2且抗体重链存在N-糖基化修饰。结合和中和活性检测结果显示A1、A2抗体的EC50分别为0.728nmol/L与0.034nmol/L，均具有一定的中和活性，可抑制病毒对细胞的杀伤。A2抗体从结合能力、中和能力方面均优于A1抗体。结论 本研究成功制备了湿地病毒Gc糖蛋白的特异性单克隆抗体，为探究湿地病毒的防治方法奠定了基础并提供科学依据。

关键词： dorsal root ganglion   IL-10   lipopolymer nanoparticle   mRNA   paclitaxel-induced peripheral neuropathy  

摘要： Paclitaxel (PTX) is a commonly used chemotherapeutic agent for treating various solid tumors;however, it often leads to a severe side effect known as paclitaxel-induced peripheral neuropathy (PIPN), for which effective treatments are limited. Although mRNA therapies have shown promise in addressing central nervous system (CNS) disorders, the successful delivery of mRNA therapeutics to the nervous system is still hindered by many biological barriers. In this study, it is demonstrated that, compared with commercial MC3 lipid nanoparticles (MC3 LNPs), mRNA-loaded P6CIT-derived lipopolymer nanoparticles (P6CIT LPNPs), which are delivered via intrathecal injection, achieve effective penetration through the pia mater. More importantly, this P6CIT LPNP demonstrates the ability to achieve highly targeted mRNA transfection in gliocytes within the spinal cord and dorsal root ganglia (DRG), which is essential for the regulation of neuroinflammation. Furthermore, two intrathecal injections of P6CIT LPNPs encapsulating mIL-10 (P6CIT/mIL-10) significantly alleviate PIPN by reducing proinflammatory cytokine production, gliocyte activation, and presynaptic NMDA receptor hyperactivity in both male and female mice. This study presents a promising and clinically translatable platform for using mRNA-loaded LPNPs to treat PIPN.

关键词： 化痰通络法   咳嗽变异性哮喘   气道重塑   白细胞介素-17   转化生长因子β1   血管内皮生长因子   血小板衍生生长因子  

摘要： 目的：研究化痰通络法对咳嗽变异性哮喘（cough variant asthma，CVA）豚鼠气道重塑相关细胞因子的影响，探讨化痰通络法治疗CVA的作用机制，为临床治疗提供依据。方法：将40只豚鼠随机分为正常组、模型组、孟鲁司特钠组及化痰通络组，以卵蛋白、氢氧化铝致敏并吸入卵蛋白激发法复制CVA豚鼠模型，观测肺组织病理形态学表现、白细胞介素-17(interleukin-17，IL-17)、转化生长因子β1(transform growth factor β1，TGF-β1)、血管内皮生长因子（vascular endothelial growth factor，VEGF）及血小板衍生生长因子（platelet-derived growth factor，PDGF)水平。结果：肉眼观察：模型组肺组织颜色暗红，个别可见瘀点、瘀斑，边缘较钝，充血水肿，体积增大，药物干预组豚鼠肺组织颜色较模型组浅，充血水肿程度较轻；HE染色：模型组肺组织支气管基底膜明显增厚，充血水肿明显，管腔变小，内可见黏液栓，炎性细胞浸润明显，支气管上皮细胞排列紊乱，肺泡壁破坏；药物干预组豚鼠肺组织支气管基底膜较模型组薄，充血水肿程度较轻，黏液栓减少，管腔相对完整且通畅，炎性细胞浸润较轻，肺泡腔较透亮；各组气道形态学参数：各组支气管基底膜周径（Pbm）组间比较无统计学差异（P＞0.05），模型组总管壁面积（Wat）较正常组增加（P＜0.05），化痰通络组较模型组Wat减小（P＜0.05），模型组管壁平滑肌面积（Wam）较正常组增加（P＜0.05），化痰通络组较模型组减小（P＜0.05），模型组Wat/Pbm、Wam/Pbm较正常组增大（P＜0.05），化痰通络组较模型组减小（P＜0.05）；细胞因子：模型组血清及支气管肺泡灌洗液（BALF）中IL-17、TGF-β1、VEGF及PDGF水平较正常组升高（P＜0.05），化痰通络组较模型组降低（P＜0.05）。结论：化痰通络法可能通过调节IL-17、TGF-β1、VEGF及PDGF水平，从而减轻气道重塑。

关键词： antibody test | Han population | human leukocyte antigen | polymorphism | Treponema pallidum  

摘要： Some associations between Treponema pallidum (TP) susceptibility and human leukocyte antigen (HLA) loci at low resolution have been reported. However, the data for TP infection and HLA alleles at high resolution are limited. The purpose of this study was to perform a high-resolution screen for HLA alleles that confer susceptibility to TP infection in the Chinese Han population. A total of 184 individuals with TP infection were included in the study, and 254 unrelated healthy blood donors were included in the control group. The samples were genotyped for the HLA-A, -C, -B, -DRB1, -DQB1 and -DPB1 loci using next-generation sequencing (NGS) technology. The correlations between TP infection and the alleles and haplotypes of HLA loci were determined by statistical analysis. Five HLA alleles, including HLA-A*32:01 (0.00% vs. 1.57%, p = 0.024), -B*52:01 (1.36% vs. 4.13%, p = 0.025), -C*01:02 (22.55% vs. 16.54%, p = 0.029), -C*04:03 (1.63% vs. 0.2%, p = 0.046) and -DQB1*05:03 (1.63% vs. 4.13%, p = 0.046), are potentially associated with TP infection. However, no significant difference was detected after p value correction. The frequency of the HLA-A*33:03-C*03:02-B*58:01-DRB1*03:01-DQB1*02:01-DPB1*05:01 haplotype in the control group was greater than that in the TP infection group (p = 0.002). In contrast, the frequency of the HLA-A*02:07-C*01:02-B*46:01-DRB1*08:03-DQB1*06:01-DPB1*02:01, HLA-A*11:01-C*03:04-B*13:01-DRB1*09:01-DQB1*03:03-DPB1*05:01, HLA-A*11:01-C*07:02-B*40:01-DRB1*08:03-DQB1*06:01-DPB1*02:01 and HLA-A*30:01-C*06:02-B*13:02-DRB1*07:01-DQB1*02:02-DPB1*02:01 haplotypes were lower in the control group than in the TP infection group (p < 0.05). HLA-C*01:02 and -C*04:03 may confer susceptibility to TP infection, whereas A*32:01, -B*52:01 and -DQB1*05:03 may protect against TP infection. These data are helpful in preventing and controlling TP transmission.

摘要： Whether one or two agents added to post-transplant cyclophosphamide (PTCy) are needed in HLA-matched allogeneic hematopoietic stem cell transplantation (allo-HSCT) with peripheral blood stem cells (PBSC) is debated. We retrospectively compared PTCy in association with a calcineurin inhibitor (PTCy+CNI) or with a CNI plus mycophenolate mofetil (PTCy+CNI+MMF) in adult patients transplanted for acute myeloid leukemia in first complete remission and receiving PBSC in the period from 2010 to 2020. Propensity score matching was performed using exact matching for donor type (related or unrelated) and the nearest neighbor for other variables (i.e. age, adverse cytogenetics, Karnofsky performance status, patient and donor cytomegalovirus serology, conditioning intensity). Each group comprised 146 patients, with 63% in total undergoing matched unrelated-allo-HSCT. Median follow up was longer for PTCy+CNI (36 [IQR 31-39] months versus 25 [IQR 19-30] months for PTCy+CNI+MMF, p < 0.01). At 2 years, PTCy+CNI was associated with a higher incidence of extensive chronic GVHD (16% [95% CI 10-22] versus 6% [95% CI 3-12] for PTCy+CNI+MMF, p < 0.03) while no differences were observed for all the other transplant outcomes. Addition of MMF to PTCy and CNI may help to prevent extensive chronic GVHD in HLA-matched allo-HSCT with PBSC.

关键词： Chronic kidney disease   Metal nephrotoxicity   Tumor necrosis factor-alpha   Gene polymorphism   Transmembrane TNF-alpha  

摘要： Chronic kidney disease (CKD) is a progressive disorder often aggravated by environmental exposure to waterborne metal pollutants, such as lead (Pb), cobalt (Co), copper (Cu), and zinc (Zn).These metals induce renal injury predominantly through oxidative stress and inflammatory pathways, with tumor necrosis factor-alpha (TNF-alpha) serving as a key mediator. The study aimed to investigate the association of the TNF-alpha -308 G/A (rs1800629) gene polymorphism and transmembrane(Tm)-TNF-alpha expression with the risk and severity of metal-induced CKD. A case-control study was conducted, including 80 patients with CKD (40 with early-stage and 40 with late-stage disease) and 40 age- and sex-matched healthy controls, selected according to stringent inclusion criteria. Metal concentrations were quantified using inductively coupled plasma mass spectrometry (ICP-MS), TNF-alpha genotyping was performed via amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), and Tm-TNF-alpha levels were assessed by flow cytometry. The findings revealed that the A allele was significantly associated with increased CKD risk across dominant, recessive, and allelic genetic models. In a co-dominant model, the AA genotype conferred a fourfold and 15-fold higher risk for early- and late-stage CKD, respectively, compared to those with the GG genotype. Moreover, elevated Tm-TNF-alpha expression was significantly associated with the GA and AA genotypes and was most pronounced in late-stage CKD patients (p < 0.001). These findings suggest that the TNF-alpha -308 G/A polymorphism markedly enhances susceptibility to metal-induced CKD, driven by increased Tm-TNF-alpha expression. Understanding this genetic variation elucidates the pathogenesis of metal-induced nephropathy and offers new opportunities for early diagnosis and targeted therapeutic development.

关键词： IL-10   IL-10R   lung inflammation   interstitial macrophages   monocyte-derived macrophages   Th1 and Th17 cells   commensal bacteria   Delftia acidovorans   Rhodococcus erythropolis   gut-lung axis  

摘要： Crosstalk between the immune system and the microbiome is critical for maintaining immune homeostasis. Here, we examined this communication and the impact of immune-suppressive IL-10 signaling on pulmonary homeostasis. We found that IL-10 sensing by interstitial macrophages (IMs) is required to prevent spontaneous lung inflammation. Loss of IL-10 signaling in IMs initiated an inflammatory cascade through the activation of classical monocytes and CD4+ T cell subsets, leading to chronic lung inflammation with age. Analyses of antibiotic-treated and germ-free mice established that lung inflammation in the animals lacking IL-10 signaling was triggered by commensal bacteria. 16S rRNA sequencing revealed Delftia acidovorans and Rhodococcus erythropolis as potential drivers of lung inflammation. Intranasal administration of these bacteria or transplantation of human fecal microbiota elicited lung inflammation in gnotobiotic Il10-deficient mice. These findings highlight that IL-10 sensing by IMs contributes to pulmonary homeostasis by preventing lung inflammation caused by commensal dysbiosis.