PD-1/PD-L1及其可溶性形式在脓毒症中的研究进展

脓毒症是宿主对感染的反应失调引起的威胁生命的器官功能障碍[1]。尽管对疾病的发病机制、治疗策略等的认识不断提升,但脓毒症仍然是重症监护病房的主要死亡病因之一[2-3]。脓毒症给全世界带来了严重的经济和社会负担,令人担忧的是未来脓毒症的发病率可能会不断增加[4]。1脓毒症的免疫抑制关于脓毒症机制的认识在不断变化。在研究的早期阶段,对于脓毒症的认识主要集中于过度活化的炎症反应,治疗策略也集中于对炎症反应的抑制,但收效甚微。许多研究通过抑制细胞因子的产生如应用IL-1、TNF阻滞剂来抑制炎症反应,但在降低病死率方面几乎没有成功甚至反而升高[5-6]。     

连续肾脏替代治疗对脓毒症炎症因子清除作用的研究进展

连续肾脏替代治疗(continuous renal replacement therapy,CRRT)是治疗脓毒症的主要方式之一,结合血液透析原理,能够有效地清除激活全身炎症反应的炎症介质、内毒素及细胞因子、补体、炎症细胞等,阻止脓毒症的发生与进展。国内外的大量研究已证实CRRT治疗脓毒症的高效性,但目前尚无可靠的生物标志物来评估其对脓毒症炎性因子的清除作用及预后。文章通过分析近年来CRRT治疗脓毒症的相关文献,总结不同炎性因子的表达特点以及脓毒症患者炎症反应的进展过程,深入了解CRRT对不同炎性因子的清除作用,以期进一步明确CRRT对脓毒症的治疗效果,从而为临床危重病中CRRT的应用提供理论基础。     

补体系统与脓毒症心肌病

脓毒症的相关研究不断取得新的进展,尤其是在动物模型研究中取得了一定的指导性成果.但由于临床实验未能提供可靠的治疗策略,导致脓毒症患者的病死率居高不下.脓毒症是一种失控的、持久性炎症反应,是由感染因素诱发的全身性炎症反应综合征(SIRS)~([1]).     

脓毒症患者炎症因子变化规律及其对预后的影响

脓毒症是由感染引起的一种全身炎症反应综合征,临床致死率极高[1]。脓毒症的发病机制尚不明确,但临床研究显示涉及全身炎症反应、免疫功能抑制、凝血功能障碍等多种机制[2]。一般认为感染原可以诱导机体生成并释放大量的炎症因子,而炎症因子可以促进级联反应并导致瀑布效应[3],扩大炎症反应,导致脓毒症[4]。本次研究通过分析脓毒症患者炎症因子表达情况,与病情严重程度和预后的关系,以期指导临床判断脓毒症病情,指导临床治疗。     

微小RNA与脓毒症发病机制研究进展

脓毒症是因感染所致的机体炎症反应失调而引起危及生命的器官功能障碍[1-2].脓毒症严重时可并发多器官功能障碍综合征( multiple organ dys-function syndrome,MODS) ,是危重症患者主要死亡原因之一.脓毒症的发病率呈逐年上升趋势,病死率为22％ ～55％ [3-4].脓毒症发病机制复杂,是多种因素相互作用的结果,主要包括肠道细菌/内毒素移位、受体与信号转导、炎症平衡失调与免疫麻痹、凝血功能障碍等.多种细胞因子、炎症介质抑制剂在动物实验研究中取得一定进展,但其临床应用的疗效仍需进一步研究证实.研究报道,微小RNA( microRNA,miRNA)可通过调控脓毒症患者炎症反应参与多器官功能损害,在脓毒症发生、发展过程中发挥重要作用[5-7].了解miRNA 对脓毒症的精细调控机制,有助于诊断脓毒症及研制特效的靶向药物,改善患者预后.本研究对 miRNA 与脓毒症发病机制研究进展作一综述,现报道如下.     

免疫麻痹与脓毒症

近年来的研究表明,抗炎反应及免疫麻痹可能是参与脓毒症致病过程的主要因素之一。免疫麻痹涉及复杂的免疫机制及细胞因子网络平衡状态改变,针对此种改变进行的免疫调节疗法可能不失为一种有效的脓毒症治疗措施。现仅就这方面的研究进展进行简要综述。脓毒症被定义为由感染引起的全身性炎症反应综合征( SIRS) ,并证实有细菌存在或有高度可疑感染灶。然而,近年来研究表明,脓毒症死亡并不全由过度的炎症反应所致,在一些脓毒症患者中可出现低下的炎症反应——“免疫麻痹”( im munoparalysis) ,由此引起迅速出现且难以控制的继发性感染也是引…     

脓毒症免疫抑制的细胞机制

全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)是指机体在各种严重感染或非感染因素刺激下产生大量的炎症介质.最终导致机体对炎症过度反应和失控所引起的一种临床综合征.而脓毒症(sepsis)是由感染引起的SIRS.近年来,人们逐渐认识到,在脓毒症的发病过程中.机体并不总是处于一成不变的炎症激活状态,免疫抑制同样是脓毒症的重要特征,它牵涉到机体天然免疫系统与获得性免疫系统.……     

重视对脓毒症免疫状态的监测与评估

脓毒症是一种失控的、持久性炎症反应,是由感染因素诱发的全身性炎性反应综合征(SIRS)。基于这种认识,人们应用大量抗炎措施治疗脓毒症,虽然在动物实验中取得了一定的疗效,但是临床应用并没有收到明显的效果。失败的原因是多方面的,但主要原因是动物模型并不能完全反映临床病情改变,人们对于机体复杂的炎症与免疫反应本质认识不足。近年来,脓毒症免疫障碍机制的研究日益受到关注,其状态与脓毒症的发展及转归息息相关。在脓毒症的发生与发展过程中,机体的免疫状态并不是一成不变的。在受到严重创伤打击后,机体可能开始处于一种免疫激活状态…     

蛋白C、活化蛋白C与脓毒症

严重脓毒症是机体对全身炎症与凝血反应的结果,可以引起多脏器功能不全,甚至死亡。近年来虽然应用更高级的抗生素、更积极的机械通气以及监护和营养支持,但严重脓毒症患者的死亡率仍居高不下。分析其原因和机制是多方面的。目前对于炎症和凝血来说,蛋白C途径日益受到关注,特别是活化蛋白C在治疗严重脓毒症中显示有较好的前景,因此,本文就蛋白C途径作一简要综述。     

组织因子和组织因子途径抑制物与脓毒症

脓毒症的发生发展过程与炎症反应、凝血及抗凝过程和免疫功能紊乱等密切相关。由组织因子（TF）所启动的外源性凝血途径不仅在脓毒症凝血反应中起关键作用，而且在炎症反应中也起着重要的作用。而组织因子途径抑制物（TFPI）则为外源性凝血过程的重要负性调节物。研究表明，TF和TFPI与脓毒症关系密切。现就TF、TFPI在脓毒症中的作用进行综述。     

Sepsis syndromes: understanding the role of innate and acquired immunity

An intact innate and acquired immune response are essential for defeating systemic microbial infections. Recognition molecules, inflammatory cells, and the cytokines they produce are the principal means for host tissues to recognize invading microbes and to initiate intercellular communication between the innate and acquired immune systems. However, activation of host innate immunity may also occur in the absence of microbial recognition, through expression of internal "danger" signals produced by tissue ischemia and necrosis. When activation of the innate immune system is severe enough, the host response itself can propel the patient into a systemic inflammatory response syndrome (SIRS), or even multiple system organ failure (MSOF) and shock. Although most patients survive the initial SIRS insult, these patients remain at increased risk of developing secondary or opportunistic infections because of the frequent onset of a compensatory anti-inflammatory response syndrome (CARS). The initial activation of the innate immune response often leads to macrophage deactivation, T-cell anergy, and the rapid apoptotic loss of lymphoid tissues, which all contribute to the development of this CARS syndrome and its associated morbidity and mortality. Initial efforts to treat the septic patient with anticytokine therapies directed at the SIRS response have been disappointing, and therapeutic efforts to modify the immune response during sepsis syndromes will require a more thorough understanding of the innate and acquired immune responses and the increased apoptosis in the lymphoid tissue.     

脓毒症相关免疫机制研究进展

随着对脓毒症免疫机制的深入研究,目前普遍认为,脓毒症的宿主免疫反应包括多个后续的或同时发生的进程,既有过度炎症,也有免疫抑制,其主要机制在于机体免疫功能紊乱,包括固有免疫及适应性免疫反应的异常,本文结合近年脓毒症在免疫机制方面的研究,从固有免疫及适应性免疫两方面探讨脓毒症时机体免疫反应的变化。     

Noncoding RNA danger motifs bridge innate and adaptive immunity and are potent adjuvants for vaccination

The adaptive immune response is triggered by recognition of T and B cell epitopes and is influenced by "danger" motifs that act via innate immune receptors. This study shows that motifs associated with noncoding RNA are essential features in the immune response reminiscent of viral infection, mediating rapid induction of proinflammatory chemokine expression, recruitment and activation of antigen-presenting cells, modulation of regulatory cytokines, subsequent differentiation of Th1 cells, isotype switching, and stimulation of cross-priming. The heterogeneity of RNA-associated motifs results in differential binding to cellular receptors, and specifically impacts the immune profile. Naturally occurring double-stranded RNA (dsRNA) triggered activation of dendritic cells and enhancement of specific immunity, similar to selected synthetic dsRNA motifs. Based on the ability of specific RNA motifs to block tolerance induction and effectively organize the immune defense during viral infection, we conclude that such RNA species are potent danger motifs. We also demonstrate the feasibility of using selected RNA motifs as adjuvants in the context of novel aerosol carriers for optimizing the immune response to subunit vaccines. In conclusion, RNA-associated motifs produced during viral infection bridge the early response with the late adaptive phase, regulating the activation and differentiation of antigen-specific B and T cells, in addition to a short-term impact on innate immunity.     

Bench-to-bedside review: Functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis

The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.     

Bench-to-bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis

The innate immune response system is designed to alert the host rapidly to the presence of an invasive microbial pathogen that has breached the integument of multicellular eukaryotic organisms. Microbial invasion poses an immediate threat to survival, and a vigorous defense response ensues in an effort to clear the pathogen from the internal milieu of the host. The innate immune system is able to eradicate many microbial pathogens directly, or innate immunity may indirectly facilitate the removal of pathogens by activation of specific elements of the adaptive immune response (cell-mediated and humoral immunity by T cells and B cells). The coagulation system has traditionally been viewed as an entirely separate system that has arisen to prevent or limit loss of blood volume and blood components following mechanical injury to the circulatory system. It is becoming increasingly clear that coagulation and innate immunity have coevolved from a common ancestral substrate early in eukaryotic development, and that these systems continue to function as a highly integrated unit for survival defense following tissue injury. The mechanisms by which these highly complex and coregulated defense strategies are linked together are the focus of the present review.     

Th1/Th2 balance in systemic inflammatory response syndrome (SIRS)

The activation of a pro-inflammatory cascade after infection, major surgery, burn or trauma appears to be important in the development of subsequent immune dysfunction, susceptibility to sepsis and multiple organ failure. It is well known that T-cell plays a critical role in the systemic response to infection. Distinct patterns of cytokines are produced by two different types of T-helper cells (Th). Th1 lymphocytes produce IFN-gamma and IL-2, favoring cell mediated immunity; Th2 cells secrete IL-4, IL-5, IL-10, IL-13, favoring humoral immunity. Cytokines produced in systemic inflammatory response syndrome (SIRS) may effect Th subset predominance and subsequent immune responses. We measured Thl/Th2 balance in patients with severe sepsis, SIRS patients with non sepsis, and healthy subjects by flow cytometry. In patients with severe sepsis, Th2 antibody mediated (humoral) immune responses predominate. We believe that severe sepsis clearly induce polarization of T-helper lymphocyte activity with a clear shift in Th2 direction. This type of response may lead immunosuppression. Modulation of Th cell subset predominance may present a novel therapeutic option in the treatment of severe sepsis.     

巨噬细胞极化在脓毒症免疫机制中的作用

脓毒症是由于感染引起的免疫功能失调，最终导致的多脏器功能障碍综合征。巨噬细胞作为先天性免疫和适应性免疫的重要组成成分之一，当微环境变化时，可分化成具有不同功能的表型，称为巨噬细胞极化。巨噬细胞极化在脓毒症的免疫调节中发挥重要作用，调控巨噬细胞极化有望成为未来脓毒症治疗的新靶点。因此，本文就巨噬细胞极化及其在脓毒症免疫机制中的作用进行综述。     

B cells enhance early innate immune responses during bacterial sepsis

Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1(-/-) mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell-deficient or anti-CD20 B cell-depleted mice, but not α/β T cell-deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell-deficient mice with serum from wild-type (WT) mice and repletion of Rag1(-/-) mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1(-/-) mice with WT, but not IFNAR(-/-), B cells improves IFN-I-dependent and -independent early cytokine responses. Repleting B cell-deficient mice with the IFN-I-dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I-activated B cells in protective early innate immune responses during bacterial sepsis.