课程文献中心 更多>>

关键词： EBV   EBNA1   HLA   GWAS   DRB1  

摘要： Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish *** IgG antibody levels against EBV nuclear antigen-1 [EBNA-1, truncated = amino acids (aa) (325-641), peptide = aa(385-420)] and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched control subjects. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM *** antibody levels against VCAp18 [odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.60-1.88] and EBNA-1, particularly the peptide (OR = 3.13, 95% CI = 2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to 12x the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g. DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as stron

关键词： l-theanine   ulcerative colitis   gut microbiota   fecal microbiotatransplantation   colon immunity   single-cell sequencing  

摘要： Alterations to the gut microbiota are associated with ulcerative colitis (UC), whereas restoration of normobiosis can effectively alleviate UC. l-Theanine has been shown to reshape the gut microbiota and regulate gut immunity. To investigate the mechanisms by which l-theanine alleviates UC, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice. In this study, we used l-theanine and l-theanine fecal microbiota solution to treat UC mice to explore the mechanism by which l-theanine alleviates UC. By reducing inflammation in the colon, we demonstrated that l-theanine alleviates symptoms of UC. Meanwhile, l-theanine can improve the abundance of microbiota related to short-chain fatty acid, bile acid, and tryptophan production. Single-cell sequencing results indicated that l-theanine-mediated suppression of UC was associated with immune cell changes, especially regarding macrophages and T and B cells, and validated the immune cell responses to the gut microbiota. Further, flow cytometry results showed that the ability of dendritic cells, macrophages, and monocytes to present microbiota antigens to colonic T cells in an MHC-II-dependent manner was reduced after treating normal mouse fecal donors with l-theanine. These results demonstrate that l-theanine modulates colon adaptive and innate immunity by regulating the gut microbiota in an MHC-II-dependent manner, thereby alleviating UC.

关键词： human leukocyte antigen   histocompatibility   molecular mismatch   eplets   kidney transplant   donor-specific antibodies  

摘要： Eplet mismatch has been recognized as a more precise strategy for determining HLA compatibility by analyzing donor-recipient HLA differences at the molecular level. However, predicting post-transplant alloimmunity using single-molecule eplet mismatch categories has not been validated in Asian cohorts. We examined a cohort of Southeast Asian kidney transplant recipients (n = 234) to evaluate HLA-DR/DQ eplet mismatch as a predictor of de novo donor-specific antibody (dnDSA) development. HLA-DR/DQ single-molecule eplet mismatch was quantified using HLA Matchmaker, and we utilized previously published HLA-DR/DQ eplet mismatch thresholds to categorize recipients into alloimmune risk groups and evaluate their association with dnDSA development. Recognizing that the predominance of cyclosporine use (71%) may alter published eplet mismatch thresholds derived from a largely tacrolimus-based (87%) cohort, we evaluated cohort-specific thresholds for HLA-DR/DQ single-molecule eplet mismatch categories. Recipient ethnicities included Chinese (65%), Malays (17%), Indians (14%), and others (4%). HLA-DR/DQ dnDSA developed in 29/234 (12%) recipients after a median follow-up of 5.4 years, including against isolated HLA-DR (n = 7), isolated HLA-DQ (n = 11), or both (n = 11). HLA-DR/DQ single-molecule eplet mismatch risk categories correlated with dnDSA-free survival (p = 0.001) with low-risk recipients having a dnDSA prevalence of 1% over 5 years. The cohort-specific alloimmune risk categories improved correlation with HLA-DR/DQ dnDSA-free survival and remained significant after adjusting for calcineurin inhibitor and anti-metabolite immunosuppression (p < 0.001). We validated the performance of single-molecule eplet mismatch categories as a prognostic biomarker for HLA-DR/DQ dnDSA development in a cohort of predominantly Asian kidney transplant recipients after adjusting for different immunosuppression regimens.

关键词： 大豆球蛋白   超高压联合酶解   抗原性   结构特性  

摘要： 以大豆中主要致敏蛋白大豆球蛋白(11S)为原料，通过不同压力条件(100～600 MPa，25 min)对其进行预处理并用复合蛋白酶水解，结合免疫学和光谱学方法探究11S处理前后抗原性及结构的变化规律。结果表明，600 MPa联合酶解处理对11S影响最大，在此条件下，11S抗原性从未处理的98.35%降到了36.69%，降低了61.66%；水解度为8.98%，11S中酸碱亚基明显被降解；二级结构中β-折叠和无规则卷曲含量显著降低，α-螺旋和β-转角含量升高；同时光谱分析发现11S三级结构发生明显变化，紫外最大吸收强度和荧光强度均显著降低并伴随着紫外光谱蓝移，荧光光谱发生红移。表明超高压联合酶解能够改变11S的构象，进而显著降低11S抗原性。研究结果可为开发低敏性大豆蛋白产品提供理论基础。

摘要： Severe defects in human IFN gamma immunity predispose individuals to both Bacillus Calmette-Gu & eacute;rin disease and tuberculosis, whereas milder defects predispose only to tuberculosis1. Here we report two adults with recurrent pulmonary tuberculosis who are homozygous for a private loss-of-function TNF variant. Neither has any other clinical phenotype and both mount normal clinical and biological inflammatory responses. Their leukocytes, including monocytes and monocyte-derived macrophages (MDMs) do not produce TNF, even after stimulation with IFN gamma. Blood leukocyte subset development is normal in these patients. However, an impairment in the respiratory burst was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)-matured MDMs and alveolar macrophage-like (AML) cells2 from both patients with TNF deficiency, TNF- or TNFR1-deficient induced pluripotent stem (iPS)-cell-derived GM-CSF-matured macrophages, and healthy control MDMs and AML cells differentiated with TNF blockers in vitro, and in lung macrophages treated with TNF blockers ex vivo. The stimulation of TNF-deficient iPS-cell-derived macrophages with TNF rescued the respiratory burst. These findings contrast with those for patients with inherited complete deficiency of the respiratory burst across all phagocytes, who are prone to multiple infections, including both Bacillus Calmette-Gu & eacute;rin disease and tuberculosis3. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but is surprisingly redundant otherwise, including for inflammation and immunity to weakly virulent mycobacteria and many other infectious agents. Human TNF is required for respiratory-burst-dependent immunity to Mycobacterium tuberculosis in macrophages but seems to be largely redundant physiologically.

关键词： 猪丁型冠状病毒   NSP9蛋白   NSP16蛋白   Ⅰ型干扰素  

摘要： 为探究猪丁型冠状病毒（PDCoV）非结构蛋白NSP9和NSP16对宿主细胞Ⅰ型干扰素（IFN-Ⅰ）的调控作用，在293T细胞中过表达NSP9、NSP16，通过双荧光素酶报告系统和qRT-PCR评估NSP9、NSP16对仙台病毒（SeV）诱导产生的IFN-β的影响，再通过qRT-PCR、Western-blot检测NSP9、NSP16对RIG-I样受体(RLRs)信号通路的影响。结果显示，NSP9、NSP16能显著抑制和降低SeV诱导的IFN-β启动子活性、IFN-β与干扰素刺激基因15（ISG15）的转录水平。同时，过表达NSP9可以显著降低RLRs信号通路中视黄酸诱导基因Ⅰ（RIG-Ⅰ）、黑色素瘤分化相关基因5（MDA5）、TANK结合激酶1（TBK1）和干扰素调节因子3（IRF3）的转录水平，并显著抑制RIG-Ⅰ、MDA5、线粒体抗病毒信号蛋白（MAVS）和TBK1的表达；而过表达NSP16可以显著降低RIG-Ⅰ和MDA5的转录水平，并显著抑制RIG-Ⅰ的表达和IRF3的磷酸化。结果表明，PDCoV的非结构蛋白NSP9和NSP16可能通过调控RLRs信号通路来抑制IFN-Ⅰ产生，本研究为阐明PDCoV的致病机制、寻找新的治疗靶点、开发新型抗病毒药物奠定理论基础。

关键词： Breast Cancer   T cell   Chemotherapy   Antibody  

摘要： Background The interleukin (IL)-1-family receptor antagonist IL-38 has emerged as a negative regulator of auto-inflammation. Given the intricate interplay between antitumor immunity and auto-inflammation, we hypothesized that blocking IL-38 may enhance tumor immune *** Our hypothesis was tested in the transgenic polyoma virus middle T oncoprotein mammary carcinoma model that is suitable for identifying strong immunomodulators. To investigate the effect of acute IL-38 blockade, we used a neutralizing antibody, alone or in combination with chemotherapy. Immune cell composition and location in tumors were determined by flow cytometry and immunohistochemistry, respectively. The role of gamma delta T cells was studied using an antibody blocking gamma delta T-cell receptor signaling. Whole transcriptome RNA sequencing and RNA expression analysis were employed to determine mechanisms downstream of IL-38 neutralization. Additionally, in vitro assays with gamma delta T cells, CD8+ T cells and cDC1, followed by in vivo CD8+ T cell depletion, were performed to study the underlying mechanistic *** Both, genetic ablation of IL-38 and neutralization with the antibody, reduced tumorigenesis, and IL-38 blockade improved chemotherapy efficacy. This was accompanied by an augmented lymphocyte infiltrate dominated by gamma delta T cells and CD8+ T cells, and signaling through the gamma delta-T-cell receptor was required for CD8+ T cell infiltration. Rather than directly interacting with CD8+ T cells, gamma delta T cells recruited conventional dendritic cells (cDC1) into tumors via the chemokine Xcl1. cDC1 in turn activated CD8+ T cells via the Notch pathway. Moreover, IL-38 negatively correlated with cDC1, XCL1-producing gamma delta T cells, T-cell infiltrates and survival in patients with mammary *** These data suggest that interfering with IL-38 improves antitumor immunity even in immunologically cold tumors.

关键词： il-17   proteobacteria   gut microbiota   type 2 diabetes mellitus   experimental periodontitis  

摘要： Objective To preliminarily explore the composition characteristics of gut microbiota in mice with type 2 diabetes mellitus (T2DM) and experimental periodontitis, and their correlation with serum IL-17 levels, aiming to provide new insights and evidence for related experimental studies. Methods A total of 42 SPF-grade C57BL/6J mice were randomly selected, with 24 used for T2DM modeling. Successfully modeled T2DM mice were divided into the T2DM group (ND group, n=8) and T2DM with experimental periodontitis group (PD group, n=8). Non-T2DM mice were divided into the blank control group (NC group, n=8) and the experimental periodontitis group (NP group, n=8). After modeling, body weight and fasting plasma glucose (FPG) were measured weekly. Each group of mice underwent an oral glucose tolerance test (OGTT) and an insulin tolerance test (ITT). Six weeks after modeling experimental periodontitis, serum IL-17 levels were measured using ELISA, intestinal inflammation was assessed using HE staining, and gut microbiota composition in cecal contents was analyzed by 16S rRNA sequencing to determine its correlation with serum IL-17 levels. Results FPG in the PD group was higher than in the ND group, with a statistically significant difference in the 12th week (p<0.05). The glucose tolerance level in the PD group was lower than in the ND group (p<0.01). Compared with the NC group, other groups showed varying degrees of inflammatory cell infiltration in the intestinal mucosa, and serum IL-17 levels were lower in both the ND and PD groups compared to the NC group (p<0.01), with the PD group also lower than the NP group (p<0.01). The Shannon and Pielou-e indices of gut microbiota in the PD group were significantly lower than those in the NP group (p<0.05). In terms of microbiota composition, Firmicutes were increased in both the ND and PD groups compared to the NC and NP groups (p<0.05), while Bacteroidetes were decreased (p<0.05). Proteobacteria were increased in the PD group compar

摘要： Interleukin-12 (IL-12) holds significant potential in cancer therapy;however, its clinical applicability is hindered by dose-limiting toxicity. Delivery of the IL-12 gene directly to tumours for constitutive IL-12 expression is a possible strategy to enhance its effectiveness while minimizing systemic toxicity. In this study, we investigate the potential of red blood cell-derived extracellular vesicles (RBCEVs) as a carrier for Il-12 plasmid delivery. We demonstrate that RBCEVs can be loaded with minicircle plasmid encoding IL-12 and delivered to MB49 bladder cancer cells for IL-12 expression. The expression of transgenes from minicircles was significantly higher than from the parental plasmids. RBCEV-mediated IL-12 expression stimulated immune responses in mouse splenocytes. Intratumoral delivery of Il-12 plasmid-loaded RBCEVs suppressed bladder cancer tumour growth, stimulated immune responses and promoted immune cell infiltration. In conclusion, our study demonstrates the promising potential of RBCEVs as an effective, safe and redosable nucleic acid drug delivery platform for IL-12.

摘要： Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel species, ( ), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the genus, with as its closest neighbor. is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to is rare for most members. displays a metabolic profile and antibiotic resistance repertoire consistent with other species. has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. Analysis of the prevalence and abundance of in >20,000 human metagenomic samples shows that it is a low-prevalence member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche, and given its interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.