PD-1/PD-L1抑制剂对肺鳞状细胞癌患者调节性T细胞及其亚型的影响

摘要 目的：探讨PD-1/PD-L1抑制剂对肺鳞状细胞癌（鳞癌）患者调节性T细胞（Regulatory T cell，Treg细胞）及其亚型的影响。方法：2019年1月至2020年12月来我院就诊的肺鳞癌初诊患者纳入本项研究；患者均接受Nivolumab治疗，根据治疗效果不同，将患者分为缓解组（n=20）和无效组（n=20）；流式细胞术检测外周血总Treg细胞、PD-1+Treg细胞、CD150+Treg细胞、CTLA-4+Treg细胞、LAG-3+Treg细胞的比例。结果：缓解组外周血总Treg细胞、CTLA-4+Treg细胞和LAG-3+Treg细胞的比例分别为4.052±0.231%、1.616±0.099%和0.328±0.021%，无效组的比例分别为5.532±0.395%、3.277±0.224%和0.857±0.108%，差异均具有显著的统计学意义（t=3.239，P=0.009；t=6.776，P＜0.001；t=4.807，P＜0.001）；缓解组外周血PD-1+Treg细胞和CD150+Treg细胞的比例分别为0.195±0.016%和1.530±0.113%，无效组的比例分别为0.203±0.018%和1.787±0.157%，差异均不具有统计学意义（t=0.318，P=0.757；t=1.329，P=0.214）。结论：PD-1/PD-L1抑制剂治疗无效的肺鳞癌患者外周血总Treg细胞、CTLA-4+Treg细胞和LAG-3+Treg细胞的比例均显著升高。     

SLE带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+FoxP3~+调节性T细胞的表达及相关性研究

目的:检测系统性红斑狼疮(systemic lupus erythematosus,SLE)合并带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+Fox P3~+调节性T细胞的表达及相关性,探讨其在SLE合并带状疱疹发病中的临床意义。方法:采用流式细胞术检测30例SLE患者、30例SLE合并带状疱疹患者及30例健康对照者外周血中CD4~+/CD8~+T淋巴细胞亚群表面CD28的表达及CD4~+CD25~+Fox P3~+Treg细胞的表达水平,并分析SLE合并带状疱疹患者外周血CD4~+CD28~+和CD4~+CD25~+Fox P3~+调节性T细胞表达的相关性。结果:SLE合并带状疱疹组患者急性期外周血CD4~+T淋巴细胞比率、绝对计数显著降低,CD4~+、CD8~+T淋巴细胞表面的CD28表达下调,CD4~+CD25~+Fox P3~+Treg细胞水平显著高于SLE组及健康对照组,SLE合并带状疱疹组患者外周血CD4~+CD25~+Fox P3~+Treg水平与CD4~+CD28~+水平成负相关(P均0.05)。结论:SLE合并带状疱疹患者CD4~+、CD8~+T细胞活化异常,CD4~+CD25~+Fox P3~+Treg细胞可能参与抑制了T细胞的活化。     

非霍奇金淋巴瘤患者外周血中CD4+CD25+ 调节性T 细胞 亚群变化初探

目的:检测非霍奇金淋巴瘤(non-Hodgkin’s lymphoma,NHL)患者外周血中CD4+CD25+调节性T细胞(CD4+CD25+regulatoryT cell,Treg)的改变,探讨Treg与NHL的相关性。方法:病例组(n=60)为本院收治的初诊NHL患者,对照组(n=60)为本院健康体检者,用流式细胞技术联合标记CD4、CD25检测对照组及病例组化疗前、化疗后的外周血中CD4+CD25+调节性T细胞的分布特点。结果:(1)病例组化疗前外周血中CD4+细胞比例显著低于对照组(P<0.05),CD4+CD25+调节性T细胞比例显著高于对照组(P<0.05);(2)病例组化疗后,CD4+细胞比例明显高于化疗前(P<0.05),CD4+CD25+调节性T细胞比例明显低于化疗前(P<0.05);(3)病例组化疗后CD4+细胞比例与对照组无显著差异(P>0.05),而CD4+CD25+调节性T细胞比例显著高于对照组(P<0.05)。结论:非霍奇金淋巴瘤患者外周血中CD4+CD25+调节性T细胞比例升高,存在机体免疫抑制,化疗可降低CD4+CD25+调节性T细胞比例。     

慢性丙型肝炎患者CD4~+CD25~+Treg细胞对树突状细胞的作用

目的探讨慢性丙型肝炎(HCV)患者CD4+CD25+Treg细胞对外周血树突状细胞的作用。方法对35例HCV患者和35例健康对照各抽取外周血,采用密度梯度离心法分离外周血单个核细胞(PBMC),采用特异性免疫磁珠分选获得CD4+CD25+Treg细胞,并体外诱导培养获得树突状细胞(DCs);将CD4+CD25+Treg细胞与DC共培养5d后,采用流式细胞仪检测DC表面标志CD83、CD80、HLADR的表达,同时酶联免疫吸附法检测上清液中IL-10和TGF-β含量。结果与健康对照组相比,HCV患者CD83、CD80和HLA-DR的表达均显著下降,差异有统计学意义(P0.01);HCV组患者CD4+CD25+Treg分泌IL-10和TGF-β的水平均高于健康组(P0.01)。结论 HCV患者外周血Treg细胞能够抑制DC的成熟,细胞因子参与了免疫应答的调节。     

嗜血细胞综合征患儿外周血CD_4~+CD_(25)~+调节性T细胞变化及临床意义

目的观察嗜血细胞综合征(hemophagocytic syndrome,HPS)患儿外周血中调节性T细胞(RegulatoryTcells,Treg细胞)的变化,探讨其在HPS发病中的作用及临床意义。方法应用流式细胞仪检测17例初诊HPS患者(初诊组)、11例经诱导治疗后临床缓解者(缓解组)及20例健康人群(对照组)外周血中CD4+CD25+调节性T细胞。结果与对照组相比较,HPS患者初诊组及缓解组外周血CD4+CD25+调节性T细胞均升高(P0.05)。与初诊组相比较,缓解组CD4+CD25+Treg细胞降低(P0.05),但仍高于正常对照组(P0.05)。结论CD4+CD25+Treg细胞增多可能是HPS患者免疫功能受抑的重要原因之一,其变化对于HPS的预后判断有一定的意义。     

PD-1/PD-L1与Treg细胞相关性的研究新进展

PD-1和PD-L属于B7家族的共刺激分子,介导免疫反应的负性调节信号。Treg细胞是一个具有免疫调节作用的T细胞亚群,在机体的免疫耐受和免疫稳定中具有重要作用。本文就PD-1/PD-L1与Treg细胞的免疫调节作用及相关性研究进展作简要综述。     

调节性T 细胞在发热结缔组织病患者外周血中的表达及临床意义

目的:研究Treg细胞在发热CTD患者外周血表达对结核感染的诊断价值。方法:对103例发热CTD患者进行T-SPOT.TB试验,将39例阳性者设为实验组-1,进行抗结核治疗,将64例阳性者设为实验组-2,另选取40例健康者作为对照组,检测三组外周血CD4+CD25+Treg细胞、Foxp3基因、IL-10、TGF-β的表达。结果:实验组CD4+CD25+Foxp3 Treg细胞占CD4+T比例高于对照组(P0.05),实验组-1治疗前外周血CD4+CD25+Foxp3 Treg细胞占CD4+T比例高于实验组-1治疗后、实验组-2(P0.05);实验组TGF-β表达量低于对照组(P0.05),实验组-1治疗前低于实验组-1治疗后及实验组-2(P0.05);实验组-1治疗前IL-10表达量低于实验组-1治疗后、实验组-2及对照组(P0.05)。结论:CD4+CD25+Foxp3 Treg细胞在发热CTD伴有结核感染患者外周血中的表达升高,其变化可作为结核感染诊断的辅助性指标。     

肾移植后恶性肿瘤患者调节性免疫细胞的变化研究

目的:探讨肾移植后发生恶性肿瘤患者调节性免疫细胞的变化。方法:收集2010年5月-2018年3月来我院进行肾移植手术的患者,肿瘤组共20例患者,病理诊断为肾脏及输尿管恶性肿瘤,对照组共20例患者,移植肾功能稳定;分离各组患者外周血淋巴细胞,流式细胞术检测调节性T细胞(Treg细胞)、调节性B细胞(Breg细胞)和滤泡调节性T细胞(Tfr细胞)的比例。结果:流式细胞学检测的结果发现,淋巴细胞中CD4~+T细胞比例在对照组和肿瘤组之间没有显著的差别(P0.05),肿瘤组中CD4+CD25+Foxp3+Treg细胞比例显著的高于对照组,增加了1.29倍(P0.05);CD19+B细胞比例在对照组和肿瘤组之间没有显著的差别(P0.05),肿瘤组中CD19+TGF-β+Breg细胞比例显著的高于对照组,增加了2.69倍(P0.05);肿瘤组中CD4+CXCR5+Foxp3+Tfr细胞比例显著的高于对照组,增加了2.74倍(P0.05)。结论:肾移植后发生恶性肿瘤患者外周血中Treg细胞、Tfr细胞和Breg细胞比例均显著升高,我们的研究为肾移植后临床用药和免疫状态的检测提供了一定的理论依据。     

幽门螺杆菌感染者CD4~+ CD25~+调节性T细胞的检测及其相关性分析

目的检测幽门螺杆菌(Helicobacter pylori,H.pylori)感染阳性的胃部疾病患者外周血中CD4+CD25+调节性T细胞(Treg细胞)的百分含量及转化生长因子-β1(transforming growth factor-β1,TGF-β1)的水平,探讨CD4+CD25+调节性T细胞在H.pylori感染中的免疫调节作用及意义。方法采用流式细胞术检测H.pylori感染的慢性浅表性胃炎、胃癌前病变和胃癌患者外周血中CD4+CD25+调节性T细胞的含量、CD4+CD25+T细胞中表达FOXP3的细胞比例;并采用ELISA方法检测H.pylori感染者血清中TGF-β1的含量,无H.pylori感染的患者作为阴性对照。结果 H.pylori感染的患者外周血中CD4+CD25+调节性T细胞的百分含量及TGF-β1的水平较不伴有H.pylori感染的患者显著升高(P<0.05);H.pylori感染的浅表性胃炎、胃癌前病变及胃癌患者外周血中CD4+CD25+T淋巴细胞的百分含量及CD4+CD25+T细胞中表达FOXP3的细胞比例随病变严重程度的进展逐渐升高,差异有统计学意义(P<0.05);H.pylori感染的患者血清中TGF-β1水平也随病变严重程度的进展逐渐升高,差异有统计学意义(P<0.05)。结论 H.pylori感染可增加CD4+CD25+调节性T细胞的含量和TGF-β1的水平;随着病变严重程度的进展,CD4+CD25+调节性T细胞的含量和TGF-β1的水平逐渐升高,CD4+CD25+调节性T细胞百分含量和TGF-β1水平可作为临床判断病情进展的指标。     

慢性阻塞性肺疾病患者外周血CD4+CD25+CD127(Low/-)调节性T细胞的检测及临床意义

目的:研究CD4+CD25+CD127(Low/-)节性T细胞在慢性阻塞性肺疾病(COPD)急性发作期外周血中的比例改变及其临床意义.方法:以25例COPD急性发作期患者外周血为研究组,20名正常人外周血作为对照组,采用三色直接荧光素标记法和多参数流式细胞仪检测外周血CD4+CD25+CD127(Low/-)调节性T细胞的比例,同时检测外周血C-反应蛋白(CRP)、血沉(ESR)、免疫球蛋白(Ig)等水平.结果:COPD急性发作期患者外周血CD4+CD25+CD127(Low/-)调节性T细胞占外周血CD4+淋巴细胞的比例明显低于健康对照组(P＜0.01).而COPD急性发作期患者外周血CRP、ESR、Ig等水平明显高于健康对照组(P＜0.05).COPD患者外周血调节T细胞下降与CRP和IgG升高成负相关.结论:COPD患者外周血CD4+CD25+CD127(Low/-)调节性T细胞在CD4+T淋巴细胞的比例明显减少,调节性T细胞等免疫调节因素可能在COPD的发病机制发挥重要作用.     

五灵胶囊联合富马酸丙酚替诺福韦片对慢性乙型肝炎患者氧化应激、CD4+CD25+调节性T细胞和血清MMP-1、MMP-2、TIMP-1的影响

摘要 目的：探讨五灵胶囊联合富马酸丙酚替诺福韦片对慢性乙型肝炎（CHB）患者氧化应激、CD4⁺CD25⁺调节性T细胞和血清基质金属蛋白酶-1（MMP-1）、基质金属蛋白酶-2（MMP-2）、基质金属蛋白酶组织抑制因子-1（TIMP-1）的影响。方法：纳入苏州大学附属传染病医院2021年6月~2022年12月期间收治的CHB患者122例,采用随机数字表法分为对照组（n=61,富马酸丙酚替诺福韦片）和研究组（n=61,五灵胶囊联合富马酸丙酚替诺福韦片）。对比两组疗效、氧化应激指标、CD4⁺CD25⁺调节性T细胞、肝功能指标[总胆红素（TBIL）、谷丙转氨酶（ALT）、谷氨酰转肽酶（GGT）]、血清MMP-1、MMP-2、TIMP-1水平和不良反应发生情况。结果：研究组的临床总有效率高于对照组（P<0.05）。两组治疗后丙二醛（MDA）下降,且研究组低于对照组同时间点;超氧化物歧化酶（SOD）升高,且研究组高于对照组同时间点（P<0.05）。两组治疗后CD4⁺CD25⁺调节性T细胞下降,且研究组低于对照组同时间点（P<0.05）。两组治疗后MMP-1、MMP-2、TIMP-1下降,且研究组低于对照组同时间点（P<0.05）。两组治疗后TBIL、ALT、GGT下降,且研究组低于对照组同时间点（P<0.05）。两组不良反应总发生率组间对比未见差异（P>0.05）。结论：五灵胶囊联合富马酸丙酚替诺福韦片治疗CHB患者,可有效减轻机体氧化应激,调节CD4⁺CD25⁺调节性T细胞和血清MMP-1、MMP-2、TIMP-1水平。     

2型糖尿病并发肺结核患者PCT、HMGB1、CD4+/CD8+比值与继发肺部感染的关系

摘要 目的：探讨2型糖尿病并发肺结核患者降钙素原（PCT）、高迁移率族蛋白1（HMGB1）、CD4⁺/CD8⁺比值与继发肺部感染的关系。方法：选择2019年1月至2022年6月四川大学华西医院呼吸与危重症医学科收治的97例2型糖尿病并发肺结核患者,根据入院治疗时是否继发肺部感染分为肺部感染组（53例）及非肺部感染组（44例）。检测两组血清PCT、HMGB1水平以及外周血CD4⁺/CD8⁺比值。单因素和多因素Logistic回归分析2型糖尿病并发肺结核患者继发肺部感染的因素。受试者工作特征（ROC）曲线分析PCT、HMGB1和CD4⁺/CD8⁺比值预测2型糖尿病并发肺结核患者继发肺部感染的价值。结果：肺部感染组血清PCT、HMGB1水平高于非肺部感染组（P＜0.05）,外周血CD4⁺/CD8⁺比值低于非肺部感染组（P＜0.05）。糖化血红蛋白及血清PCT、HMGB1水平升高是2型糖尿病并发肺结核患者继发肺部感染的危险因素（P＜0.05）,高CD4⁺/CD8⁺比值是保护因素（P＜0.05）。PCT、HMGB1、CD4⁺/CD8⁺比值预测2型糖尿病并发肺结核患者继发肺部感染的曲线下面积为0.719、0.761、0.738,联合PCT、HMGB1和CD4⁺/CD8⁺比值预测的曲线下面积为0.878,高于各指标单独预测。结论：2型糖尿病并发肺结核患者血清PCT、HMGB1水平增高,外周血CD4⁺/CD8⁺比值降低,均与继发肺部感染有关,PCT、HMGB1联合CD4⁺/CD8⁺比值可辅助预测2型糖尿病并发肺结核患者继发肺部感染的风险。     

Foxp3+ Regulatory T Cells among Tuberculosis Patients: Impact on Prognosis and Restoration of Antigen Specific IFN-γ Producing T Cells

CD4⁺CD25⁺Foxp3⁺ Regulatory T cells (Treg) and programmed death-1 (PD-1) molecules have emerged as pivotal players in immune suppression of chronic diseases. However, their impact on the disease severity, therapeutic response and restoration of immune response in human tuberculosis remains unclear. Here, we describe the possible role of Treg cells, their M. tuberculosis driven expansion and contribution of PD-1 pathway to the suppressive function of Treg cells among pulmonary tuberculosis (PTB) patients. Multicolor flow cytometry, cell culture, cells sorting and ELISA were employed to execute the study. Our results showed significant increase in frequency of antigen-reactive Treg cells, which gradually declined during successful therapy and paralleled with decline of M. tuberculosis–specific IL-10 along with elevation of IFN-γ production, and raising the IFN-γ/IL-4 ratio. Interestingly, persistence of Treg cells tightly correlated with MDR tuberculosis. Also, we show that blocking PD-1/PD-L1 pathway abrogates Treg-mediated suppression, suggesting that the PD-1/PD-L1 pathway is required for Treg-mediated suppression of the antigen-specific T cells. Treg cells possibly play a role in dampening the effector immune response and abrogating PD-1 pathway on Treg cells significantly rescued protective T cell response, suggesting its importance in immune restoration among tuberculosis patients.     

脾氨肽联合普米克令舒对小儿支气管哮喘的临床疗效及对CD4+, CD8+, IgE水平的影响

目的:分析脾氨肽联合普米克治疗小儿支气管哮喘的临床疗效及对患儿CD4~+、CD8~+、血清Ig E水平的影响。方法:选取我院2015年6月~2016年10月收治的支气管哮喘急性发作患儿88例,采用随机数字法将其分为对照组和观察组,每组各44例。所有患儿进行止咳化痰治疗,对照组患儿在此基础上采用雾化吸入普米克令舒混悬液,观察组患儿在对照组用药基础上加用脾氨肽口服冻干粉。比较两组患儿的临床疗效、症状消失时间、肺功能变化情况、住院时间及治疗前后CD4~+、CD8~+、CD 4~+/CD8~+及血清Ig E水平的变化。结果:观察组的治疗总有效率显著高于对照组(P0.01)。治疗后,观察组的咳嗽、胸部哮鸣音、喘憋消失时间及住院时间均明显短于对照组(P0.01),FVC、FEV1及FEV/FVC、CD4~+、CD4~+/CD8~+水平均显著高于对照组(P0.01),而血清Ig E浓度明显低于对照组(P0.01)。两组不良反应发生率及CD8~+水平比较差异无统计学意义(P0.05)。结论:脾氨肽联合普米克令舒可显著提高小儿支气管哮喘的临床疗效,迅速改善患儿的临床症状及免疫功能,且安全性高。     

The effect of Curcumin on multi-level immune checkpoint blockade and T cell dysfunction in head and neck cancer

BackgroundDespite recent advances in understanding the complex immunologic dysfunction in the tumor microenvironment (TME), fewer than 20% of patients with head and neck squamous cell carcinoma (HNSCC) respond to immune checkpoint blockade (ICB). Thus, it is important to understand how inhibitory IC receptors maintain the suppressed dysfunctional TME, and to develop more effective combination immunotherapy. This study evaluated the immune-modulating effects of Curcumin, which has well-established anti-cancer and chemopreventive properties, and its long-term safety as a phytochemical drug.MethodsWe carried out the western blot and small interfering RNA (siRNA) transfection assay to evaluate the effects of Curcumin on IC ligands and IC ligands function in HNSCC. Through T-cell cytotoxicity assay and measurements of cytokine secretion, we assessed the effects of combination of Curcumin with programmed death-ligand 1 (PD-L1) Ab on cancer cell killing. Flow cytometry were used to analyze the effects of Curcumin on the expression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain3 (TIM-3) on CD4, CD8 and Treg. Immunofluorescence, immunohistochemistry and western blot were used to detecte the cytokine (IFN-γ, Granzyme B), IC receptors (PD-1 and TIM-3) and its ligands (PD-L1, PD-L2, Galectin-9) in xenograft mouse model and 4-nitroquinoline-1-oxide (4-NQO) oral cancer model.ResultsWe found that Curcumin decreased the expression of IC ligands such as PD-L1, PD-L2, and Galectin-9 in HNSCC, leading to regulation of epithelial-to-mesenchymal transition-associated tumor invasion. Curcumin also effectively restored the ability of CD8⁺ cytotoxic T cells to lyse cancer cells. To evaluate the effect of Curcumin on the TME further, the 4-NQO oral cancer model was used. Curcumin increased T-cell proliferation, tumor-infiltrating lymphocytes (TILs), and effector cytokines, and decreased the expression of PD-1, TIM-3, suppressive IC receptors and their ligands (PD-L1, PD-L2, and Galectin-9) in the TME, implying reinvigoration of the exhausted CD8⁺ T cells. In addition, Curcumin inhibited expression of CD4⁺CD25⁺FoxP3⁺ Treg cells as well as PD-1 and TIM-3.ConclusionsThese results show that Curcumin reinvigorates defective T cells via multiple (PD-1 and TIM-3) and multi-level (IC receptors and its ligands) IC axis suppression, thus providing a rationale to combine Curcumin with conventional targeted therapy or ICB as a multi-faceted approach for treating patients with HNSCC.     

Bone marrow-derived mesenchymal stem cells promote cell proliferation of multiple myeloma through inhibiting T cell immune responses via PD-1/PD-L1 pathway

Objectives: This study aims to explore the effect of bone marrow mesenchymal stem cells (BMSCs) on multiple myeloma (MM) development and the underlying mechanism.

Materials and Methods: BMSCs from C57BL/6 J mice were isolated and the third passage was used for subsequent experiments. Additionally, a series of in vitro transwell coculture assays were performed to explore the effects of BMSCs on the proliferation of MM cells 5TGM1 and CD4⁺ T cells. Furthermore, a 5TGM1-induced MM mice model was established. Moreover, PD-L1 shRNA was transfected into BMSCs to investigate whether PD-1/PD-L1 pathway involved in BMSCs-mediated regulation of T cells and MM growth.

Results: Data revealed that BMSCs significantly promoted 5TGM1 proliferation in a dose-dependent manner. Furthermore, BMSCs administration exerted stimulatory effects on MM development in terms of shortening the mouse survival rate, promoting tumor growth, and enhancing inflammatory infiltration in the MM model mice. Moreover, BMSCs decreased the percentage of Th1 and Th17 cells, whereas increased that of Th2 and Treg cells. Their corresponding cytokines of these T cell subsets showed similar alteration in the presence of BMSCs. Additionally, BMSCs significantly suppressed CD4⁺ T cell proliferation. We also found that PD-L1 shRNA inhibited 5TGM1 proliferation likely through activation of CD4⁺ T cells. Further in vivo experiments confirmed that PD-L1 inhibition attenuated BMSCs-induced MM growth, inflammation infiltration and imbalance of Th1/Th2 and Th17/Treg.

Conclusion: In summary, our findings demonstrated that BMSCs promoted cell proliferation of MM through inhibiting T cell immune responses via PD-1/PD-L1 pathway.     

Association of PARP-1, NF-κB,NF-κBIA and IL-6, IL-1β and TNF-α with Graves Disease and Graves Ophthalmopathy

Background

Graves Disease (GD) is an autoimmune disorder affected by an interaction of multiple genes such as Nuclear Factor-κB (NF-κB), Nuclear Factor-κB Inhibitor (NF-κBIA), Poly (ADP-ribose) polymerase-1 (PARP-1) and cytokines like Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and Tumor Necrosis Factor-α (TNF-α) and mostly accompanied by an ocular disorder, Graves Ophthalmopathy (GO). We hypothesize that there is a relationship between GD, GO, polymorphisms of inflammatory related genes and their association with cytokines, which may play important roles in autoimmune and inflammatory processes.

Subjects and methods

To confirm our hypothesis, we studied the polymorphisms and cytokine levels of 120 patients with GD and GO using PCR-RFLP and ELISA methods, respectively.

Results

We found that patients with GG genotype and carriers of G allele of PARP-1 G1672A polymorphism are at risk in the group having GD (p = 0.0007) while having GA genotype may be protective against the disease. PARP-1 C410T polymorphism was found to be associated with GO by increasing the risk by 1.7 times (p = 0.004). Another risk factor for development of GO was the polymorphism of del/ins of NFkB1 gene (p = 0.032) that increases the risk by 39%. Levels of cytokines were also elevated in patients with GD, but no association was found between levels of cytokines and the development of GO as there was no change in levels of cytokines.

Conclusions

We suggest that, PARP-1 and NFkB1 gene polymorphisms may be risk factors for developing Graves Disease and Ophthalmopathy.     

Myeloid-derived suppressor cells regulate the immunosuppressive functions of PD-1−PD-L1+ Bregs through PD-L1/PI3K/AKT/NF-κB axis in breast cancer

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells that are closely related to tumor immune escape, but the mechanism by which MDSCs regulate B cells has not been elucidated. Our previous studies revealed that breast cancer-derived MDSCs could induce a group of PD-1⁻PD-L1⁺ Bregs with immunosuppressive functions. Here, we reported that blocking PD-1/PD-L1 interaction between MDSCs and B cells could reverse the immunosuppressive functions of PD-1⁻PD-L1⁺ Bregs. The activation of PI3K/AKT/NF-κB signaling pathway is essential for PD-1⁻PD-L1⁺ Bregs to exert immunosuppressive effects. MDSCs activated the PI3K/AKT/NF-κB pathway in B cells via the PD-1/PD-L1 axis. Furthermore, inhibition of PD-1/PD-L1 or PI3K/AKT signaling suppressed both tumor growth and the immunosuppressive functions of PD-1⁻PD-L1⁺ Bregs. Dual suppression of PD-1/PD-L1 and PI3K/AKT exerted better antitumor effect. Finally, MDSCs and PD-1⁻PD-L1⁺ Bregs were colocalized in breast cancer tissues and PD-1⁻PD-L1⁺ Bregs were positively correlated with poor prognosis. Thus, MDSC-educated PD-1⁻PD-L1⁺ Bregs and their regulatory mechanisms could contribute to the immunosuppressive tumor microenvironment. Our study proposes a novel mechanism for MDSC-mediated regulation of B cell immunity, which might shed new light on tumor immunotherapy.⁺Subject terms: Breast cancer, Cancer microenvironment     

肺炎支原体肺炎伴喘息儿童血清25(OH)D_3、Th17/Treg表达水平与肺功能的关系

目的:探讨肺炎支原体肺炎伴喘息儿童血清25羟基维生素D3[25(OH)D_3]、辅助性17细胞/调节性T细胞(Th17/Treg)表达水平与肺功能的关系。方法:将新疆医科大学第五附属医院收治的肺炎支原体肺炎伴喘息患儿26例作为肺炎伴喘息组,肺炎支原体肺炎不伴有喘息患儿54例作为肺炎不伴喘息组,另选取健康儿童30例作为对照组,比较各组血清25(OH)D_3、白细胞介素(IL)-10、IL-17、Th17细胞及Treg细胞占CD4+T细胞比例及肺功能,并分析其相关性。结果:肺炎伴喘息组血清25(OH)D_3、IL-10、Treg细胞占CD4+T细胞比例低于肺炎不伴喘息组、对照组,Th17细胞占CD4+T细胞比例、Th17/Treg、IL-17高于肺炎不伴喘息组、对照组(P0.05)。各组第一秒最大呼气量占用力肺活量百分比(FEV1/FVC)比较差异无统计学意义(P0.05),肺炎伴喘息组FEV1占预计值百分比(FEV1%pred)、峰值呼气流量(PEF)低于肺炎不伴喘息组、对照组(P0.05),肺炎不伴喘息组与对照组FEV1%pred、PEF比较无统计学意义(P0.05)。肺炎伴喘息组患儿血清25 (OH)D_3与Th17/Treg、IL-17呈负相关(P0.05),与IL-10、FEV1%pred、PEF呈正相关(P0.05),血清Th17/Treg与IL-10、FEV1%pred、PEF呈负相关(P0.05),与IL-17呈正相关(P0.05)。结论:肺炎支原体肺炎伴喘息儿童血清25(OH)D_3、Th17/Treg表达水平异常,肺功能下降,且25(OH)D_3、Th17/Treg表达水平与肺功能相关。