Loss of Jak2 Selectively Suppresses DC-Mediated Innate Immune Response and Protects Mice from Lethal Dose of LPS-Induced Septic Shock

Given the importance of Jak2 in cell signaling, a critical role for Jak2 in immune cells especially dendritic cells (DCs) has long been proposed. The exact function for Jak2 in DCs, however, remained poorly understood as Jak2 deficiency leads to embryonic lethality. Here we established Jak2 deficiency in adult Cre^+/+Jak2^fl/fl mice by tamoxifen induction. Loss of Jak2 significantly impaired DC development as manifested by reduced BMDC yield, smaller spleen size and reduced percentage of DCs in total splenocytes. Jak2 was also crucial for the capacity of DCs to mediate innate immune response. Jak2^−/− DCs were less potent in response to inflammatory stimuli and showed reduced capacity to secrete proinflammatory cytokines such as TNFα and IL-12. As a result, Jak2^−/− mice were defective for the early clearance of Listeria after infection. However, their potency to mediate adaptive immune response was not affected. Unlike DCs, Jak2^−/− macrophages showed similar capacity secretion of proinflammatory cytokines, suggesting that Jak2 selectively modulates innate immune response in a DC-dependent manner. Consistent with these results, Jak2^−/− mice were remarkably resistant to lethal dose of LPS-induced septic shock, a deadly sepsis characterized by the excessive innate immune response, and adoptive transfer of normal DCs restored their susceptibility to LPS-induced septic shock. Mechanistic studies revealed that Jak2/SATA5 signaling is pivotal for DC development and maturation, while the capacity for DCs secretion of proinflammatory cytokines is regulated by both Jak2/STAT5 and Jak2/STAT6 signaling.     

PiCCO监测在感染性休克患者中的应用研究

目的:通过对感染性休克患者进行Pi CCO监测,对比CVP与GEDVI对循环血容量的判断价值,探讨Pi CCO治疗方案在感染性休克早期液体复苏中的应用价值。方法:选取入ICU时APACHEⅡ大于15分的感染性休克患者18例,行气管插管机械通气。经锁骨下静脉置管,经股动脉置入股动脉型热稀释导管,行Pi CCO监测。Pi CCO建立即刻为T0,每小时一次热稀释测量,连续测量6小时(T1~T6)。以CI、GEDVI、EVLWI为指导,按Pi CCO治疗方案进行液体管理。结果:以GEDVI为金标准,CVP对低血容量判断的灵敏度、特异度、阳性预测值、阴性预测值分别是4%、100%、100%、64%。CVP对高血容量判断的灵敏度、特异度、阳性预测值、阴性预测值分别是17%、55%、21%、48%。CVP与CI无相关性,ΔCVP与ΔCI无相关性,CVP与GEDVI无相关性。而GEDVI与CI明显相关,ΔGEDVI与ΔCI明显相关。GEDVI与EVLWI有相关性,而CVP与EVLWI无相关性.在各时点,CI与GEDVI变化趋势基本一致,而CI与CVP变化趋势相反。结论:对于需要机械通气的感染性休克患者,CVP对低血容量判断的特异度高,但不灵敏。GEDVI能够更好的反映心脏的前负荷,对低血容量的判断敏感,更适合感染性休克病人的液体管理。Pi CCO治疗治疗方案可以避免因CVP不敏感而导致的液体复苏不足现象的发生。     

不同麻醉方式对急性腹膜炎伴感染性休克患者围麻醉期影响的临床对比研究

目的：探讨不同麻醉方式对急性腹膜炎伴感染性休克患者围麻醉期的影响性,以期提高临床麻醉水平。方法：回顾性分析2011年2月-2012年12月50例急性腹膜炎伴感染性休克患者,对分成2组,对照组予以气管内插管静脉吸入复合全麻组,观察组予以硬膜外阻滞麻醉＋复合全麻组,观察2组麻醉后在各个麻醉循环系数的变化和不良反应情况。结果：两组在入室时在心率、MAP和SpO：比较无明显差异性（P〉0．05）,而麻醉后在MAP各个时期以及拔管时在心率上比较有明显差异性（P〈0．05）,有统计学意义,SpO2却均在95％以上,比较无差异性（P〉0．05）;在临床效果上,对照组的优良率为60％,总有效率为72％,苏醒时间为（16．5±2．7）min;观察组的优良率为86％,总有效率为100％,苏醒时间为（3．7±1．3）min两组比较有明显的差异性（P〈0．05）;而在不良反应上,在恶心呕吐和呼吸抑制上比较有明显差异性（P〈0．05）;而在疼痛和烦躁上比较无明显差异性（P〉0．05）。结论：硬膜外阻滞麻醉＋复合全麻对急性腹膜炎伴感染性休克患者围麻醉期效果良好．安全性好。     

MicroRNA调控固有免疫应答的分子机制

MicroRNA（miRNA）是近几年继siRNA之后非编码RNA研究的又一热点．它通过与靶mRNA的特异性结合,在转录后水平上对基因表达进行调控．研究表明,miRNA可能参与脊椎动物固有免疫应答的多个环节．在病原微生物感染时,它们不仅成为重要的固有免疫受体活化后的信号调节分子,而且能够直接干扰病毒复制而发挥抗病毒效应．miRNA可能与经典的固有免疫应答体系共同组成机体抵御病原微生物入侵的“第一道防线”．同时,病原微生物,特别是病毒还可以通过自己编码miRNA或者改变宿主细胞miRNA表达谱直接或间接地干扰很多宿主免疫相关基因的表达,实现逃逸机体免疫清除的目的．因此,miRNA水平的相瓦作用可能是病原微生物与其宿丰展开免疫“博弈”的重要战场．     

Plant Innate Immune Response: Qualitative and Quantitative Resistance

Plant diseases, caused by microbes, threaten world food, feed, and bioproduct security. Plant resistance has not been effectively deployed to improve resistance in plants for lack of understanding of biochemical mechanisms and genetic bedrock of resistance. With the advent of genome sequencing, the forward and reverse genetic approaches have enabled deciphering the riddle of resistance. Invading pathogens produce elicitors and effectors that are recognized by the host membrane-localized receptors, which in turn induce a cascade of downstream regulatory and resistance metabolite and protein biosynthetic genes (R) to produce resistance metabolites and proteins, which reduce pathogen advancement through their antimicrobial and cell wall enforcement properties. The resistance in plants to pathogen attack is expressed as reduced susceptibility, ranging from high susceptibility to hypersensitive response, the shades of gray. The hypersensitive response or cell death is considered as qualitative resistance, while the remainder of the reduced susceptibility is considered as quantitative resistance. The resistance is due to additive effects of several resistance metabolites and proteins, which are produced through a network of several hierarchies of plant R genes. Plants recognize the pathogen elicitors or receptors and then induce downstream genes to eventually produce resistance metabolites and proteins that suppress the pathogen advancement in plant. These resistance genes (R), against qualitative and quantitative resistance, can be identified in germplasm collections and replaced in commercial cultivars, if nonfunctional, based on genome editing to improve plant resistance.     

固有免疫应答与动脉粥样硬化关系的研究进展

固有免疫应答在动脉粥样硬化(atherosclerosis,As)的发生和发展中起重要作用．固有免疫应答细胞,包括单核/巨噬细胞、肥大细胞、自然杀伤细胞、中性粒细胞和树突状细胞,是机体抵御微生物和异物入侵的第一道防线．这些细胞广泛参与As中泡沫细胞形成、斑块内基质降解、细胞凋亡、血管新生和斑块破裂等事件．模式识别受体是免疫细胞上识别病原体(或某些内源性成分)相关分子模式的一类受体分子,包括Toll样受体和NOD样受体,介导固有免疫应答反应．Toll样受体在固有免疫应答细胞中具有不同程度的表达,在As中具有不同的作用,如TLR2和TLR4对As起促进作用,而TLR3具有As保护作用．NLRP3炎性体与动脉血管壁的早期损伤有关．对固有免疫应答细胞及模式识别受体在As形成中的作用进行深入研究,不仅有助于理解As的形成过程,而且还能为临床上防治心血管类疾病提供了新的治疗靶点和诊断指标．     

肝脏固有免疫系统对肠源性感染的免疫应答与免疫耐受机制

肝特殊的解剖结构及生理特征使其成为暴露肠源性抗原的主要器官。由于肝具有独特的固有免疫系统,在正常情况下,肝分布多种致耐受的抗原提呈细胞,对持续性表达或递呈于肝的肠源性抗原物质,诱发针对该抗原的系统性免疫耐受,避免肝受到不必要的免疫损伤。当炎症发生及肝脏固有免疫系统活化时,则通过免疫效应细胞及免疫效应因子对肠源性病原体发挥强烈地免疫应答以控制感染。该过程形成机制的研究对肝功能的理解及肝性疾病的预防与治疗至关重要。本文就肝固有免疫系统对肠源性感染的免疫应答与免疫耐受形成机制作一综述。     

Voriconazole Versus Amphotericin B as Induction Therapy for Talaromycosis in HIV/AIDS Patients: A Retrospective Study

Mycopathologia - Disseminated talaromycosis caused by Talaromyces marneffei is a life-threatening opportunistic infection. Although amphotericin B deoxycholate (dAmB) remains the first-line...     

The Antiviral Innate Immune Response in Fish: Evolution and Conservation of the IFN System

Innate immunity constitutes the first line of the host defense after pathogen invasion. Viruses trigger the expression of interferons (IFNs). These master antiviral cytokines induce in turn a large number of interferon-stimulated genes, which possess diverse effector and regulatory functions. The IFN system is conserved in all tetrapods as well as in fishes, but not in tunicates or in the lancelet, suggesting that it originated in early vertebrates. Viral diseases are an important concern of fish aquaculture, which is why fish viruses and antiviral responses have been studied mostly in species of commercial value, such as salmonids. More recently, there has been an interest in the use of more tractable model fish species, notably the zebrafish. Progress in genomics now makes it possible to get a relatively complete image of the genes involved in innate antiviral responses in fish. In this review, by comparing the IFN system between teleosts and mammals, we will focus on its evolution in vertebrates.     

CRRT治疗剂量对脓毒症休克合并急性肾损伤患者免疫功能及预后的影响

目的:探讨连续性肾脏替代治疗(Continuous renal replacement therapy,CRRT)治疗剂量对脓毒症休克合并急性肾损伤(acute kidney injury,AKI)患者免疫功能及预后的影响。方法:选择2016年3月到2017年12月我院ICU科收治的脓毒症休克合并急性肾损伤(AKI)患者120例,随机分为高剂量组、中剂量组、低剂量组和对照组四组,每组各30例。对照组采用常规治疗,低剂量组采用20 m L/kg CRRT治疗,中剂量组采用35 m L/kg CRRT治疗,高剂量组采用60 m L/kg CRRT治疗。比较4组治疗前后肾功能、免疫功能指标、APACHEⅡ(Acute Physiology and Chronic Health EvaluationⅡ, APACHEⅡ)评分和SOFA(sequential organ failure assessment)评分分数的变化。结果:治疗后,各组患者血尿素氮(blood urea nitrogen,BUN)和血肌酐(Serum creatinine,Scr)水平、APACHEⅡ评分和SOFA评分均较治疗前显著降低(P0.05),且高剂量组BUN、Scr、APACHEⅡ评分和SOFA评分均显著低于其他3组(P0.05),中剂量组和低剂量组以上指标均显著低于对照组(P0.05),而低剂量组BUN和Scr明显低于对照组(P0.05)。治疗后,各组患者CD3+、CD4+百分比及CD4+/CD8+比值均较治疗前显著升高(P0.05),且高剂量组CD3+、CD4+百分比及CD4+/CD8+比值高于其他3组(P0.05),中剂量组以上指标显著高于低剂量组和对照组(P0.05),低剂量组以上指标明显高于对照组(P0.05)。结论:连续性肾脏替代治疗能显著改善脓毒症合并急性肾损伤患者肾功能和免疫功能,且效果呈一定的剂量依赖性。     

医疗机构推诿艾滋病病毒感染者/艾滋病病人应对策略

通过分析非定点医疗机构推诿艾滋病病毒感染者和艾滋病病人的表现形式和发展过程,认为：政策落实不到位、监督机制不健全、定点医疗机构诊疗能力弱、非定点医疗机构维护自我利益、相关保障机制不健全等是医疗机构推诿的主要原因。在分析的基础上,提出了解决的策略：完善政策、提高定点医疗机构的诊疗能力、加强培训、完善防护措施、健全补偿机制、加强与病人的沟通、加大监督力度。     

Acute Kidney Injury in Severe Sepsis and Septic Shock in Patients with and without Diabetes Mellitus: A Multicenter Study

IntroductionWhether diabetes mellitus increases the risk of acute kidney injury (AKI) during sepsis is controversial.ResultsFirst, we compared 451 patients with severe sepsis or septic shock and diabetes to 3,277 controls with severe sepsis or septic shock and without diabetes. Then, we compared 318 cases (with diabetes) to 746 matched controls (without diabetes). Diabetic patients did not have a higher frequency of AKI (hazard ratio [HR], 1.18; P = 0.05]) or RRT (HR, 1.09; P = 0.6). However, at discharge, diabetic patients with severe sepsis or septic shock who experienced acute kidney injury during the ICU stay and were discharged alive more often required RRT (9.5% vs. 4.8%; P = 0.02), had higher serum creatinine values (134 vs. 103 µmoL/L; P<0.001) and had less often recovered a creatinine level less than 1.25 fold the basal creatinine (41.1% vs. 60.5%; P<0.001).ConclusionsIn patients with severe sepsis or septic shock, diabetes is not associated with occurrence of AKI or need for RRT but is an independent risk factor for persistent renal dysfunction in patients who experience AKI during their ICU stay.     

Molecular Profiling of Innate Immune Response Mechanisms in Ventilator-associated Pneumonia

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Highlights

• •ETA present a diverse proteome and metabolome and can be employed for longitudinal studies of nosocomial infections affecting the lungs.
• •The proteome and metabolome of ETA and BAL share comparable features that may be leveraged for diagnostics.
• •ETA carries early signatures of host innate immunity against ventilator-associated pneumonia.

     

An Impaired Inflammatory and Innate Immune Response in COVID-19

The recent appearance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected millions of people around the world and caused a global pandemic of coronavirus disease 2019 (COVID-19). It has been suggested that uncontrolled, exaggerated inflammation contributes to the adverse outcomes of COVID-19. In this review, we summarize our current understanding of the innate immune response elicited by SARS-CoV-2 infection and the hyperinflammation that contributes to disease severity and death. We also discuss the immunological determinants behind COVID-19 severity and propose a rationale for the underlying mechanisms.     

Detection of Innate Immune Response Modulating Impurities in Therapeutic Proteins

Therapeutic proteins can contain multiple impurities, some of which are variants of the product, while others are derived from the cell substrate and the manufacturing process. Such impurities, even when present at trace levels, have the potential to activate innate immune cells in peripheral blood or embedded in tissues causing expression of cytokines and chemokines, increasing antigen uptake, facilitating processing and presentation by antigen presenting cells, and fostering product immunogenicity. Currently, while products are tested for host cell protein content, assays to control innate immune response modulating impurities (IIRMIs) in products are focused mainly on endotoxin and nucleic acids, however, depending on the cell substrate and the manufacturing process, numerous other IIRMI could be present. In these studies we assess two approaches that allow for the detection of a broader subset of IIRMIs. In the first, we use commercial cell lines transfected with Toll like receptors (TLR) to detect receptor-specific agonists. This method is sensitive to trace levels of IIRMI and provides information of the type of IIRMIs present but is limited by the availability of stably transfected cell lines and requires pre-existing knowledge of the IIRMIs likely to be present in the product. Alternatively, the use of a combination of macrophage cell lines of human and mouse origin allows for the detection of a broader spectrum of impurities, but does not identify the source of the activation. Importantly, for either system the lower limit of detection (LLOD) of impurities was similar to that of PBMC and it was not modified by the therapeutic protein tested, even in settings where the product had inherent immune modulatory properties. Together these data indicate that a cell-based assay approach could be used to screen products for the presence of IIRMIs and inform immunogenicity risk assessments, particularly in the context of comparability exercises.     

1225例HIV/AIDS患者流行病学特征分析

目的:了解来陕西地区就诊的人类免疫缺陷病毒/艾滋病(Human immunodeficiency virus/Acquired immuno deficiency syndrome,HIV/AIDS)患者感染状况、流行特征。方法:收集来我院就诊的HIV/AIDS患者的基本信息,对其流行病学资料统计分析。结果:在调查的1225例HIV/AIDS患者中,男性占83.51%,平均年龄为(35.55±11.61)岁,50.98%为农民,小学及以下学历占33.55%,经血液途径感染250例,经性传播途径感染916例,其中同性性传播337例,经母婴垂直传播16例,就诊时CD4+T淋巴细胞计数平均值为(222.82±190.49)个/μL,56%的HIV/AIDS患者采用的抗病毒方案为齐多夫定(Zidovudine,AZT)/替诺福韦(Tenofovir Disoproxil Fumarate,TDF)+拉米夫定(Lamivudine,3TC)+依非韦伦(Efavirenz,EFV)方案。结论:陕西地区HIV/AIDS感染人数呈上升趋势,且年轻化加剧,同性性传播比例大幅增加。虽然治疗较为及时,应进一步在高危人群中积极宣传防艾知识与措施。