Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indi...Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.展开更多
Background:Post–cardiac arrest syndrome involves systemic inflammation,which causes subsequent neurological impairments.We investigated the influence of targeted temperature management(TTM)therapy in patients with ou...Background:Post–cardiac arrest syndrome involves systemic inflammation,which causes subsequent neurological impairments.We investigated the influence of targeted temperature management(TTM)therapy in patients with out-of-hospital cardiac arrest(OHCA)after return of spontaneous circulation(ROSC)by observing the changes in circulating CD14^(+)monocytes and the expression of human leukocyte antigen D–related(HLA-DR)and programmed cell death ligand 1(PD-L1)in CD14^(+)monocytes.Methods:Adult patients admitted to the emergency department of Beijing Chao-Yang Hospital after OHCA between January 2017 and March 2018 were included in this study.Thirty control subjects,10 patients with OHCA,and 37 patients with OHCA who received 72 hours of TTM therapy were enrolled.Peripheral blood samples of patients in the OHCA and TTM groups were collected on Days 1 and 3(D1 and D3)after ROSC and evaluated for HLA-DR and PD-L1 expression on CD14^(+)monocytes using flow cytometry.Results:Compared with control subjects,the percentage of circulating CD14^(+)monocytes,HLA-DR+/CD14^(+)monocyte ratios,and mean fluorescence intensity were significantly decreased in patients with OHCA.After ROSC,HLA-DR expression in CD14^(+)monocytes in the TTM group was lower than that in patients with OHCA.However,there were no significant differences in the percentage of PD-L1+/CD14^(+)monocytes or the mean fluorescence intensity between patients with OHCA and healthy volunteers.Conclusion:After ROSC,circulating CD14^(+)monocytes and HLA-DR+/CD14^(+)monocyte ratios decreased significantly in patients with OHCA.Human leukocyte antigen D–related expression in CD14^(+)monocytes was lower in patients treated with TTM.展开更多
目的:探讨监测CD14+单核细胞人白血病抗原DR(monocyte human leukocyte antigen-DR,mHLA-DR)表达在评估重症肺炎患者预后中的价值。方法:挑选38例重症肺炎患者,以明确诊断后28天的预后作为标准分成生存组(22例)与死亡组(16例),另选择38...目的:探讨监测CD14+单核细胞人白血病抗原DR(monocyte human leukocyte antigen-DR,mHLA-DR)表达在评估重症肺炎患者预后中的价值。方法:挑选38例重症肺炎患者,以明确诊断后28天的预后作为标准分成生存组(22例)与死亡组(16例),另选择38例健康者纳入对照组。在重症肺炎确诊后第1、3、5、7天,应用流式细胞术连续监测患者外周血mHLA-DR的表达;对照组在研究期间常规检测1次mHLA-DR表达。结果:重症肺炎患者确诊后第1天,生存组与死亡组mHLA-DR表达均明显低于对照组(P<0.05)。生存组mHLA-DR表达呈逐渐升高趋势,到第7天生存组mHLA-DR表达已接近对照组水平,两者差异已无统计学意义(P>0.05);而死亡组mHLA-DR表达持续偏低,在各个时间点始终低于对照组,差异均有统计学意义(P<0.05)。相同时间点死亡组mHLA-DR表达均低于生存组,差异均有统计学意义(P<0.05)。以确诊第1天mHLA-DR表达<30%预测重症肺炎患者死亡的敏感度为93.8%,特异度为81.8%。结论:重症肺炎患者确诊后第1天mHLA-DR表达<30%可作为预测患者预后不佳的指标,另外连续监测病程中不同时间点的mHLA-DR表达对重症肺炎患者预后的评估也有一定的价值。展开更多
This study examined the effect of intensive insulin therapy on immune function and inflammatory factors at the early phase after severe trauma. At day 1, 3, 5, 7 after admission, subsets of CD4＋ helper T lymphocytes ...This study examined the effect of intensive insulin therapy on immune function and inflammatory factors at the early phase after severe trauma. At day 1, 3, 5, 7 after admission, subsets of CD4＋ helper T lymphocytes （Th1/Th2） and human leukocyte antigen （HLA）-DR expression on CD14＋ monocytes were flow cytometrically measured. Levels of cytokines, including tumor necrosis factor-alpha （TNF-α）, interleukin-6 （IL-6）, interleukin-10 （IL-10） and other immunity markers, such as IgA, IgG, IgM, C3, C4 and C reaction protein （CRP） were examined in two groups. The results showed that TNF-α, IL-6 and CRP levels in the intensive insulin therapy group were significantly lower than those in the conventional therapy group, whereas IL-10 levels were substantially increased after intensive insulin therapy. C3 level at day 3, 5, 7 and C4 levels at day 5, 7 were lower in the intensive therapy group than in the conventional therapy group. Th1/Th2 ratios decreased gradually over time in both groups, and were much lower at day 3, 5, 7 in intensive therapy group. There were significant differences among day 3 to day 7 after admission in HLA-DR expression in CD14＋ monocytes. It was concluded that the intensive insulin therapy could decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines in the elderly suffering from severe trauma, at the same time, with complement recovery being delayed. Moreover, intensive insulin therapy promoted immune suppression and, therefore, measures need be taken to address the issue.展开更多
基金supported by the Key Project of National Natural Science Foundation of China(82130062,82241062 and 81930057)the National Key Research and Development Program of China(2022YFA1104604)+1 种基金the Key Project of Military Medical Innovation Program of Chinese PLA(18CXZ026 and BLJ18J006)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-076)。
文摘Background Sustained yet intractable immunosuppression is commonly observed in septic patients,resulting in aggravated clinical outcomes.However,due to the substantial heterogeneity within septic patients,precise indicators in deciphering clinical trajectories and immunological alterations for septic patients remain largely lacking.Methods We adopted cross-species,single-cell RNA sequencing(scRNA-seq)analysis based on two published datasets containing circulating immune cell profile of septic patients as well as immune cell atlas of murine model of sepsis.Flow cytometry,laser scanning confocal microscopy(LSCM)imaging and Western blotting were applied to identify the presence of S100A9^(+)monocytes at protein level.To interrogate the immunosuppressive function of this subset,splenic monocytes isolated from septic wild-type or S100a9^(–/–)mice were co-cultured with naive CD4^(+)T cells,followed by proliferative assay.Pharmacological inhibition of S100A9 was implemented using Paquinimod via oral gavage.Results scRNA-seq analysis of human sepsis revealed substantial heterogeneity in monocyte compartments following the onset of sepsis,for which distinct monocyte subsets were enriched in disparate subclusters of septic patients.We identified a unique monocyte subset characterized by high expression of S100A family genes and low expression of human leukocyte antigen DR(HLA-DR),which were prominently enriched in septic patients and might exert immunosuppressive function.By combining single-cell transcriptomics of murine model of sepsis with in vivo experiments,we uncovered a similar subtype of monocyte significantly associated with late sepsis and immunocompromised status of septic mice,corresponding to HLA-DR^(low)S100A^(high)monocytes in human sepsis.Moreover,we found that S100A9^(+)monocytes exhibited profound immunosuppressive function on CD4^(+)T cell immune response and blockade of S100A9 using Paquinimod could partially reverse sepsis-induced immunosuppression.Conclusions This study identifies HLA-DR^(low)S100A^(high)monocytes correlated with immunosuppressive state upon septic challenge,inhibition of which can markedly mitigate sepsis-induced immune depression,thereby providing a novel therapeutic strategy for the management of sepsis.
基金the National Natural Science Foundation of China(Grant No.81372025).
文摘Background:Post–cardiac arrest syndrome involves systemic inflammation,which causes subsequent neurological impairments.We investigated the influence of targeted temperature management(TTM)therapy in patients with out-of-hospital cardiac arrest(OHCA)after return of spontaneous circulation(ROSC)by observing the changes in circulating CD14^(+)monocytes and the expression of human leukocyte antigen D–related(HLA-DR)and programmed cell death ligand 1(PD-L1)in CD14^(+)monocytes.Methods:Adult patients admitted to the emergency department of Beijing Chao-Yang Hospital after OHCA between January 2017 and March 2018 were included in this study.Thirty control subjects,10 patients with OHCA,and 37 patients with OHCA who received 72 hours of TTM therapy were enrolled.Peripheral blood samples of patients in the OHCA and TTM groups were collected on Days 1 and 3(D1 and D3)after ROSC and evaluated for HLA-DR and PD-L1 expression on CD14^(+)monocytes using flow cytometry.Results:Compared with control subjects,the percentage of circulating CD14^(+)monocytes,HLA-DR+/CD14^(+)monocyte ratios,and mean fluorescence intensity were significantly decreased in patients with OHCA.After ROSC,HLA-DR expression in CD14^(+)monocytes in the TTM group was lower than that in patients with OHCA.However,there were no significant differences in the percentage of PD-L1+/CD14^(+)monocytes or the mean fluorescence intensity between patients with OHCA and healthy volunteers.Conclusion:After ROSC,circulating CD14^(+)monocytes and HLA-DR+/CD14^(+)monocyte ratios decreased significantly in patients with OHCA.Human leukocyte antigen D–related expression in CD14^(+)monocytes was lower in patients treated with TTM.
文摘目的:探讨监测CD14+单核细胞人白血病抗原DR(monocyte human leukocyte antigen-DR,mHLA-DR)表达在评估重症肺炎患者预后中的价值。方法:挑选38例重症肺炎患者,以明确诊断后28天的预后作为标准分成生存组(22例)与死亡组(16例),另选择38例健康者纳入对照组。在重症肺炎确诊后第1、3、5、7天,应用流式细胞术连续监测患者外周血mHLA-DR的表达;对照组在研究期间常规检测1次mHLA-DR表达。结果:重症肺炎患者确诊后第1天,生存组与死亡组mHLA-DR表达均明显低于对照组(P<0.05)。生存组mHLA-DR表达呈逐渐升高趋势,到第7天生存组mHLA-DR表达已接近对照组水平,两者差异已无统计学意义(P>0.05);而死亡组mHLA-DR表达持续偏低,在各个时间点始终低于对照组,差异均有统计学意义(P<0.05)。相同时间点死亡组mHLA-DR表达均低于生存组,差异均有统计学意义(P<0.05)。以确诊第1天mHLA-DR表达<30%预测重症肺炎患者死亡的敏感度为93.8%,特异度为81.8%。结论:重症肺炎患者确诊后第1天mHLA-DR表达<30%可作为预测患者预后不佳的指标,另外连续监测病程中不同时间点的mHLA-DR表达对重症肺炎患者预后的评估也有一定的价值。
基金supported by a grant from the National Natural Sciences Foundation of China(No.30700869)
文摘This study examined the effect of intensive insulin therapy on immune function and inflammatory factors at the early phase after severe trauma. At day 1, 3, 5, 7 after admission, subsets of CD4＋ helper T lymphocytes （Th1/Th2） and human leukocyte antigen （HLA）-DR expression on CD14＋ monocytes were flow cytometrically measured. Levels of cytokines, including tumor necrosis factor-alpha （TNF-α）, interleukin-6 （IL-6）, interleukin-10 （IL-10） and other immunity markers, such as IgA, IgG, IgM, C3, C4 and C reaction protein （CRP） were examined in two groups. The results showed that TNF-α, IL-6 and CRP levels in the intensive insulin therapy group were significantly lower than those in the conventional therapy group, whereas IL-10 levels were substantially increased after intensive insulin therapy. C3 level at day 3, 5, 7 and C4 levels at day 5, 7 were lower in the intensive therapy group than in the conventional therapy group. Th1/Th2 ratios decreased gradually over time in both groups, and were much lower at day 3, 5, 7 in intensive therapy group. There were significant differences among day 3 to day 7 after admission in HLA-DR expression in CD14＋ monocytes. It was concluded that the intensive insulin therapy could decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines in the elderly suffering from severe trauma, at the same time, with complement recovery being delayed. Moreover, intensive insulin therapy promoted immune suppression and, therefore, measures need be taken to address the issue.
