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
By def inition, sepsis refers to a life threatening organ dysfunction due to a dysregulated host response to an infection[1]. More precisely, sepsis triggers a multifaceted response characterized by a simultaneous man...By def inition, sepsis refers to a life threatening organ dysfunction due to a dysregulated host response to an infection[1]. More precisely, sepsis triggers a multifaceted response characterized by a simultaneous manifestation of proinflammatory and anti-inflammatory elements that disrupt mechanisms intended to maintain homeostasis. Initially, an overwhelming hyperinflammatory reaction ensues, resulting in tissue damage and organ dysfunction.展开更多
Patients with obstructive jaundice have a high susceptibility to infection in the process of treatment and the reason for this is not fully understood. It was postulated that it may bear some relations to abnormalitie...Patients with obstructive jaundice have a high susceptibility to infection in the process of treatment and the reason for this is not fully understood. It was postulated that it may bear some relations to abnormalities of immune function. In this article. 28 cases of obstructive jaundice were selected to investigate alternation of monocyte immune function with the purpose of exploring mechanism of high susceptibility to infection from the perspective of immunology. The results showed that interleukin 1 production by monocytes significantly decreased and prostaglandin E2 increased, HLA-DR expression of monocytes was markably depressed. HLA-DR expression of monocytes was further decreased with recovery slower than non-jaundiced patients after operation. All this may be responsible for high susceptibility to infection in the process of treatment of obstructive jaundice .展开更多
目的:研究严重创伤进展为持续炎症-免疫抑制-分解代谢综合征(persistent inflammation,immunosuppression and catabolism syndrome,PICS)的影响因素,并构建PICS发生风险的列线图预测模型并评估其预测效果。方法:收集新疆医科大学第一...目的:研究严重创伤进展为持续炎症-免疫抑制-分解代谢综合征(persistent inflammation,immunosuppression and catabolism syndrome,PICS)的影响因素,并构建PICS发生风险的列线图预测模型并评估其预测效果。方法:收集新疆医科大学第一附属医院TICU 2017年6月—2023年5月收治的169例严重创伤患者资料。根据ICU住院第14天的C反应蛋白、淋巴细胞计数和白蛋白水平将患者分为PICS组(78例)和非PICS组(91例)。收集了患者的入院初次诊断指标、血栓弹力图、血小板指标及生化指标,使用独立样本t检验、Mann-Whitney U检验和χ2检验进行单因素分析,再进行多因素logistic分析确定严重创伤并发PICS的危险因素;使用R软件建立列线图预测模型,通过受试者工作特征曲线下面积(area under curve,AUC)和拟合度检验评估模型预测效果。结果:在169例严重创伤患者中,78例发展为PICS,91例未发展为PICS。两组在年龄、年龄评分、最大振幅(maximum amplitude,MA)、凝固角、血块30 min溶解百分比、血液凝固时间、血小板平均分布宽度、血小板计数、血小板压积、总蛋白、球蛋白、总胆固醇及γ谷氨酰胺基转肽酶(γ-glutamyl transferase,γ-GGT)方面差异有统计学意义(P<0.05)。多因素logistic回归分析显示,血小板平均分布宽度(platelet distribution width,PDW)、MA、γ-GGT是严重创伤并发PICS的独立影响因素(H-L检验0.847,正确百分比74%),使用这些独立危险因素建立的列线图模型具有较好区分度及校准度(AUC=0.787,MAE=0.053)。结论:PDW、MA、γ-GGT是严重创伤并发PICS的独立影响因素。基于这些指标构建的列线图模型能较好预测严重创伤患者发生PICS的可能性,有助于早期识别和阻止PICS的发生发展。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.
文摘By def inition, sepsis refers to a life threatening organ dysfunction due to a dysregulated host response to an infection[1]. More precisely, sepsis triggers a multifaceted response characterized by a simultaneous manifestation of proinflammatory and anti-inflammatory elements that disrupt mechanisms intended to maintain homeostasis. Initially, an overwhelming hyperinflammatory reaction ensues, resulting in tissue damage and organ dysfunction.
文摘Patients with obstructive jaundice have a high susceptibility to infection in the process of treatment and the reason for this is not fully understood. It was postulated that it may bear some relations to abnormalities of immune function. In this article. 28 cases of obstructive jaundice were selected to investigate alternation of monocyte immune function with the purpose of exploring mechanism of high susceptibility to infection from the perspective of immunology. The results showed that interleukin 1 production by monocytes significantly decreased and prostaglandin E2 increased, HLA-DR expression of monocytes was markably depressed. HLA-DR expression of monocytes was further decreased with recovery slower than non-jaundiced patients after operation. All this may be responsible for high susceptibility to infection in the process of treatment of obstructive jaundice .
文摘目的:研究严重创伤进展为持续炎症-免疫抑制-分解代谢综合征(persistent inflammation,immunosuppression and catabolism syndrome,PICS)的影响因素,并构建PICS发生风险的列线图预测模型并评估其预测效果。方法:收集新疆医科大学第一附属医院TICU 2017年6月—2023年5月收治的169例严重创伤患者资料。根据ICU住院第14天的C反应蛋白、淋巴细胞计数和白蛋白水平将患者分为PICS组(78例)和非PICS组(91例)。收集了患者的入院初次诊断指标、血栓弹力图、血小板指标及生化指标,使用独立样本t检验、Mann-Whitney U检验和χ2检验进行单因素分析,再进行多因素logistic分析确定严重创伤并发PICS的危险因素;使用R软件建立列线图预测模型,通过受试者工作特征曲线下面积(area under curve,AUC)和拟合度检验评估模型预测效果。结果:在169例严重创伤患者中,78例发展为PICS,91例未发展为PICS。两组在年龄、年龄评分、最大振幅(maximum amplitude,MA)、凝固角、血块30 min溶解百分比、血液凝固时间、血小板平均分布宽度、血小板计数、血小板压积、总蛋白、球蛋白、总胆固醇及γ谷氨酰胺基转肽酶(γ-glutamyl transferase,γ-GGT)方面差异有统计学意义(P<0.05)。多因素logistic回归分析显示,血小板平均分布宽度(platelet distribution width,PDW)、MA、γ-GGT是严重创伤并发PICS的独立影响因素(H-L检验0.847,正确百分比74%),使用这些独立危险因素建立的列线图模型具有较好区分度及校准度(AUC=0.787,MAE=0.053)。结论:PDW、MA、γ-GGT是严重创伤并发PICS的独立影响因素。基于这些指标构建的列线图模型能较好预测严重创伤患者发生PICS的可能性,有助于早期识别和阻止PICS的发生发展。
