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关键词： T(H)17   anxiety   depression   gut leakage   interleukin-22   psychological stress   septal neurons   the septal area  

摘要： Psychological stress and its sequelae pose a major challenge to public health. Immune activation is conventionally thought to aggravate stress-related mental diseases such as anxiety disorders and depression. Here, we sought to identify potentially beneficial consequences of immune activation in response to stress. We showed that stress led to increased interleukin (IL)-22 production in the intestine as a result of stress-induced gut leakage. IL-22 was both necessary and sufficient to attenuate stress-induced anxiety behaviors in mice. More specifically, IL-22 gained access to the septal area of the brain and directly suppressed neuron activation. Furthermore, human patients with clinical depression displayed reduced IL-22 levels, and exogenous IL-22 treatment ameliorated depressive-like behavior elicited by chronic stress in mice. Our study thus identifies a gut-brain axis in response to stress, whereby IL-22 reduces neuronal activation and concomitant anxiety behavior, suggesting that early immune activation can provide protection against psychological stress.

关键词： Oncolytic virus   Cytokine   Abscopal   Intratumoral   T cell  

摘要： Background Interleukin-18 (IL-18), or interferon (IFN)-gamma-inducing factor, potentiates T helper 1 and natural killer cell activation as well as CD8+ T-cell proliferation. Recombinant IL-18 has displayed limited clinical efficacy in part due to the expression of the decoy receptor, IL-18 binding protein (IL-18BP). A series of IL-18 variants that are devoid of IL-18BP binding, termed DR18 (decoy-resistant IL-18), was developed via directed evolution. We tested DR18 using oncolytic adenovirus (oAd) as a platform for delivery in syngeneic mouse tumor *** oAd harboring wild-type IL-18 or DR18 (oAdDR18) was constructed by inserting IL-18 mutant into modified oAd backbone with Ad5/3 chimeric fiber. The delivery effect and IFN-gamma induction were determined by ELISA. The antitumor efficiency of oAdDR18 was tested in CT26, B16BL6 and 4T1 tumor-bearing mice, or athymic nude mice and compared with recombinant DR18 protein (rDR18). 4T1 lung metastasis model was used to evaluate the antitumor efficiency of local and distant tumors. Antitumor memory and synergistic effect with an anti-programmed cell death protein-1 (PD-1) antibody was evaluated. The phenotypes of the immune cells in tumor microenvironment were analyzed by flow cytometry and *** Mice received oAdDR18 maintained stable production of IL-18 and IFN-gamma compared with those received rDR18. Intratumoral delivery of oAdDR18 significantly reduced tumor growth across several tumor models, but not in the athymic nude mouse model. Mice that had tumor remission showed antitumor memory. The antitumor effect was associated with intratumor infiltration of CD4+ and CD8+ T cells. DR18 delivered by oAd demonstrated long-lasting and enhanced antitumor activities against local and distant tumors compared with that received rDR18 or wild-type IL-18 delivered by oAd (oAdwtIL-18). oAdDR18 treatment also reduced 4T1 lung metastasis. In addition, combination of this virotherapy with immune checkp

关键词： 中性粒细胞   淋巴细胞比值   类风湿关节炎   预后   Neutrophil   Lymphocyte Ratio   Rheumatoid Arthritis   Prognosis  

摘要： 中性粒细胞/淋巴细胞比值(NLR)是一种新型非特异性炎症指标，其通过测定外周血中的中性粒细胞和淋巴细胞的计数比值来评估机体的免疫状态。目前被用于各种良恶性肿瘤、心血管疾病、感染性疾病和免疫系统疾病的早期诊断和预后监测。而类风湿关节炎(RA)是第二常见的慢性关节炎性疾病，以对称性侵袭性关节、滑膜炎症为主。作为高致残性的疾病，类风湿性关节炎的早期诊断、病情监测对于患者的预后结局有着重要作用。临床中对于疾病的监测涉及多种生物标记物，其中本文就NLR在RA中的作用进行综述，以期为炎症指标在RA中的价值提供新的见解。

关键词： 急性B淋巴细胞白血病   儿童   免疫表型   微小残留病  

摘要： 目的 探究第19天（D19）微小残留病（MRD）与急性B淋巴细胞白血病（B-ALL）患儿预后的关系及与相关生物学改变的联系。方法 统计2016年4月至2020年4月于该院初诊符合入组条件的88例B-ALL患儿诱导治疗D19 MRD、总生存（OS）率、无事件生存（EFS）率、染色体核型、融合基因和突变基因，以MRD≥0.01%为阳性，分为阳性组和阴性组，比较两组3年OS、EFS、免疫表型和分子生物学/细胞遗传学特点。结果 88例患儿3年OS和EFS分别为92.0%和86.4%，MRD阳性组OS及EFS率均低于阴性组，差异有统计学意义（P＜0.05）。MRD阳性组中CD10表达率低于阴性组，差异有统计学意义（P＜0.05）。32例（36.4%）患儿检出8种35个融合基因。MRD阳性组中BCR-ABL1、E2A-PBX1检出率均高于阴性组，差异有统计学意义（P＜0.05）；48例（54.5%）患儿检出41种91个突变基因，余突变基因均＜5例；18例（20.5%）患儿检出异常染色体核型，17例无核分裂相，正常和异常核型MRD无区别。经二分类Logistic回归分析，MRD阳性组BCR-ABL1、E2A-PBX1检出率均高于阴性组，差异有统计学意义（P<0.05）。结论 D19 MRD阳性是B-ALL患儿OS和EFS不良的影响因素；CD10低表达、E2A-PBX1、BCR-ABL1均对B-ALL患儿预后有不良影响。

关键词： 黄曲霉毒素B   抗原   单克隆抗体   量子点   电化学发光  

摘要： 食品和粮食中黄曲霉毒素B1(aflatoxinB1，AFB1)的现场快速检测是当前亟待解决的研究课题。该研究设计了一种结合AFB1单克隆抗体与CdTe量子点材料的电化学传感器，建立了量子点单克隆抗体（quantumdotmonoclonalantibody，QBS-mAb）用于AFB1的可视化快速定量筛查检测方法。当AFB1抗原与AFB1偶联的比例为50:1时，QBS-mAb法的检测范围为0.03～12 μg/L，最低检测限（limitofdetection，LOD）为0.03μg/L。该方法具有较高的灵敏度、宽广的线性范围，回收率在84.62%～114.47%，并且与现行国家标准GB5009.22—2016《食品安全国家标准 食品中黄曲霉毒素B族和G族的测定》检测结果表现出高度一致性。该研究建立的QBS-mAb方法实现了食品和粮食的现场即时检测，旨在提升基层监管机构的日常筛查检测水平。

关键词： 降钙素基因相关肽   偏头痛   预防性治疗   安全性   比例失衡法  

摘要： 目的：挖掘抗降钙素基因相关肽 (calcitonin gene-related peptide， CGRP)/其受体（CGRPR）单克隆抗体药物（Erenumab，EM、Galcanezumab，GM、Fremanezumab，FM和Eptinezumab，EP) 的安全警戒信号，从药物不良事件（adverse drug event，ADE）信号角度比较4种药物在安全性上的差异，为临床安全合理用药提供参考。方法：利用报告比值比（ROR）法和比例报告比值（PRR）法对美国FDA不良事件报告系统（FAERS）中2020年第1季度至2023年第3季度中的4种药物ADE报告进行数据挖掘，重点评估和比较神经、皮肤、胃肠道和心血管等重点系统的安全警戒信号。结果：经筛选处理后得到以抗CGRP/CGRPR单克隆抗体为首要怀疑药物（primary suspect drug，PS）的ADE报告数分别是EM 15 875例、GM 8 854例、FM 2 268例和EP 1 983例，整理计算后得到有效ADE信号分别为46、68、43、40个；EM在胃肠和肌肉系统的风险信号强度较其他药物最显著，心血管系统风险信号最多；GM在皮肤和神经系统风险信号强度较其他药物最显著；FM在肌肉系统未见高危信号；EP在心血管系统风险信号强度较其他药物最显著；EP除妊娠的风险信号显著，未见其他高危信号，其余3种药物均有生殖系统相关ADE的发生风险。结论：临床应用抗CGRP/CGRPR单克隆抗体类药物时应加强对患者心血管事件风险的监测；女性患者应注意月经异常等现象；应用EM、GM时，应密切关注雷诺现象和肌肉不适等现象。通过对该类药物的ADE信号挖掘，分析比较了该类药物的ADE信号风险，有助于降低临床用药风险，提高临床用药选择性。

关键词： breast cancer   chronic stress   exosomes   lung metastasis   neutrophils  

摘要： Chronic stress can significantly promote breast cancer progression. When exposed to chronic stress, exosomes released from neural and neuroendocrine cells in the central nervous system are enhanced and modified. However, whether tumor-derived exosomes (TDEs) are influenced by chronic stress and participate in chronic stress-mediated distant metastasis remains unclear. Here, it is shown that chronic stress remarkably facilitates the secretion of TDEs and modifies the contents of exosomes by activating the adrenergic beta receptor in 4T1 tumor-bearing mice. Exosomes injection and blockade experiments indicate that exosomes play a crucial role in chronic stress-mediated lung metastasis of breast cancer. Chronic stress-induced TDEs are internalized by pulmonary neutrophils and strengthen neutrophil recruitment via the CXCL2 autocrine. In addition, the level of SP1 in TDEs increases, which favors the secretion of IL-1 beta by neutrophils through the activation of the TLR4-NF kappa beta pathway, ultimately aggravating lung metastasis of breast cancer. Collectively, this study provides a novel mechanism by which neutrophils within a pre-metastatic niche acquire their inflamed phenotype and establishes an important link among neuroendocrine changes, exosomes, immunity, and metastasis.

关键词： IL-5   ILC2   IgA   commensal bacteria   eosinophil  

摘要： Intestinal bacteria play a critical role in the regulation of the host immune system and an imbalance in intestinal bacterial composition induces various host diseases. Therefore, maintaining a balance in the intestinal bacterial composition is crucial for health. Immunoglobulin A (IgA), produced through T cell-dependent and T cell-independent (TI) pathways, is essential for host defense against pathogen invasion and maintaining the balance of intestinal symbiotic bacteria. Interleukin (IL)-5 is constitutively produced by group 2 innate lymphoid cells (ILC2s) and plays a critical role in the survival and proliferation of B cells and eosinophils. Here, we show that the role of IL-5-producing ILC2s in intestinal TI IgA production at steady state using TCRα deficient mice. In this mouse model, ILC2s increased fecal TI IgA levels in a non-inflammatory state in an IL-5-dependent manner. The administration of recombinant IL-33 (rIL-33) increased the amount of TI IgA production, accompanied by an increase in the number of IL-5-producing ILC2s in the large intestine. In addition, rIL-33 treatment increased IL-5-dependent IgA+ cells in isolated lymphoid follicles, the site of TI IgA production. Furthermore, eosinophils recruited by ILC2s were required for the maximal production of IgA in the TI pathway. Moreover, IL-5 increased the frequency of TI IgA-binding intestinal bacteria and was involved in the maintenance of intestinal bacterial composition. These findings indicate that IL-5-producing ILC2s together with eosinophils contribute to TI IgA production. In addition to their role in TI IgA production, IL-5-producing ILC2s may contribute to the homeostasis of intestinal commensal bacteria.

关键词： IL-33   IL-25   ILC2   Trained immunity   Th2 adaptive immunity   Lung inflammation  

摘要： While Th2 adaptive immunity has long been considered to orchestrate type 2 inflammation in the allergic lung, group 2 innate lymphoid cells (ILC2s), with the ability to produce a similar profile of type 2 cytokines, likely participate in lung inflammation in allergic asthma. ILC2s are also implicated in sex disparities in asthma, supported by data from murine models showing they are inhibited by male sex hormones. Moreover, larger numbers of ILC2s are present in the lungs of female mice and are correlated with greater type 2 inflammation. Lung ILC2s exhibit intriguing memory-like responses, though whether these differ in males and females does not appear to have been addressed. We have examined type 2 lung inflammation in adult male and female Balb/c mice following delivery of IL-33 to the lung. While the number of ILC2s was elevated equally in males and females four weeks after exposure to IL-33, ILC2s from female mice expressed higher levels of ST2, the IL-33 cognate receptor subunit, and a larger proportion of ILC2s from females expressed the IL-25 receptor (IL-25R), which has previously been linked to memory-like ILC2 responses in mice. Our data show that the subset of ILC2s expressing IL-25R, upon activation, was more likely to produce IL-5 and IL-13. Moreover, STAT6 was absolutely required for enhanced responsiveness in this model system. Altogether, our data show that enhanced type 2 inflammation in females is linked to durable changes in ILC2 subsets with the ability to respond more robustly, in a STAT6-dependent manner, upon secondary activation by innate epithelial-derived cytokines.

关键词： 骨膜蛋白   白细胞介素33   冠状动脉旁路移植术   胸腔镜肺叶切除术   慢性咳嗽  

摘要： 目的 探讨Periostin、白介素-33(interleukin-33,IL-33)与冠状动脉旁路移植术（coronary artery bypass grafting,CABG）合并肺癌患者胸腔镜肺叶切除术后慢性咳嗽的相关性。方法 前瞻性纳入天津市胸科医院2022年1月—2024年1月102例肺癌患者，依据术后是否出现慢性咳嗽的情况，分为慢性咳嗽组与非慢性咳嗽组。于肺叶切除术后的第1天、第7天及第14天检测患者血清中的Periostin和IL-33水平。Pearson法分析Periostin和IL-33和咳嗽严重程度的相关性。通过单因素及多因素logistic回归分析，识别影响慢性咳嗽发生的因素。利用受试者工作特征（receiver operating characteristic,ROC）曲线分析评估血清中Periostin和IL-33水平对预测术后慢性咳嗽的潜在价值。结果 在慢性咳嗽组中，第7天和第14天测定的外周血Periostin和IL-33水平显著高于非慢性咳嗽组，两组之间及不同时间点的交互作用均显著（P<0.001）。咳嗽程度与第7天和第14天的Periostin及IL-33水平呈正相关（P<0.05），而与第1天的水平无显著关联（P>0.05）。肺癌患者在胸腔镜肺叶切除后，第7天的Periostin[OR=1.619,95%CI(1.295,2.025)]和IL-33[OR=1.831,95%CI(1.216,2.758)]以及第14天的Periostin[OR=1.952,95%CI(1.306,2.918)]和IL-33[OR=1.742,95%CI(1.166,2.603)]为慢性咳嗽的风险因素。ROC曲线分析表明，第7天Periostin的灵敏度为69.05%，特异度为71.67%,AUC为0.756[95%CI(0.616,0.893)]；第14天的Periostin灵敏度提高到71.43%，特异度为76.67%,AUC为0.762[95%CI(0.633,0.898)]；第7天的IL-33临界值为45.03 pg/mL，灵敏度和特异度均为83.33%,AUC为0.884[95%CI (0.789,0.980)]；第14天的IL-33临界值为56.01 pg/mL，灵敏度为85.71%，特异度为80.00%,AUC为0.899[95%CI(0.799,0.999)]。进一步的回归分析显示，灵敏度为95.24%，特异度为95.00%,AUC达到0.993[95%CI(0.979,1.000)]。结论 在不同时间点测定的Periostin与IL-33，在CABG合并胸腔镜肺叶切除术后呈现异常高表达，并与肺癌患者咳嗽的严重度显著相关，可应用于预测慢性咳嗽。