细胞因子风暴:急性呼吸窘迫综合征中的主宰生命之手

细胞因子风暴是机体对于病毒、细菌、纳米材料等外界刺激所产生的一种过度免疫。急性呼吸窘迫综合征(acute respiratory distress syndrome,ARDS)的发病原因是由于细胞因子风暴造成的肺毛细血管内皮细胞以及肺泡上皮细胞的弥漫性损伤。多种病毒感染,如SARS冠状病毒、2009甲型H1N1流感病毒、禽流感病毒,以及某些纳米材料,均可导致细胞因子风暴,进而引起ARDS。目前临床上对于细胞因子风暴与ARDS尚无特异性治疗手段,多采用给予抗感染药物、糖皮质激素等非特异性联合治疗措施。靶向治疗,如应用单克隆抗体、核酸适配体或特异的重组蛋白等措施,是未来的治疗方向。     

白细胞介素-37在流感病毒感染导致的重症肺炎中作用的研究进展

流感是由流感病毒引起的急性呼吸道传染病,流感病毒感染机体过程中,常因免疫反应过度促使细胞因子大量分泌,形成细胞因子风暴,导致肺损伤、肺衰竭甚至死亡.流感病毒感染导致的重症肺炎是流感患者死亡的重要原因之一,目前临床上用于流感治疗的药物主要是抗病毒药物,通常不能调控机体的过度免疫反应,也不能减轻肺部的炎症损伤.白细胞介素-...     

SARS-CoV-2引发缺血性脑卒中的机制研究进展

新型冠状病毒（Severe acute respiratory syndrome coronavirus 2,SARS-CoV-2）目前仍在全球肆虐传播，在引发2019新冠肺炎（Corona virus disease 2019,COVID-19）的同时，还能造成感染者中枢神经系统的损伤。缺血性脑卒中是COVID-19相关神经系统损伤常见病之一。本文归纳出SARS-CoV-2进入中枢的途径，以及该病毒是如何通过介导氧化应激反应、肾素-血管紧张素系统的失调、攻击血管内皮细胞、激活NLRP3炎症小体、释放中性粒细胞胞外陷阱、引发细胞因子风暴等一系列分子机制导致缺血性脑卒中的发病，以期为疾病的临床预防和治疗提供一些新的见解和思路。     

脐带间充质干细胞治疗新型冠状病毒肺炎2例

新型冠状病毒感染疫情,已经发展为全球公共卫生紧急事件。世界卫生组织将此病毒命名为2019新型冠状病毒(2019-nCoV),将引发的疾病命名为2019冠状病毒病(Coronavirus Disease-19,COVID-19)。COVID-19患者以发热、乏力、干咳为主要临床表现,少数患者伴有鼻塞、流涕和腹泻等症状。重症患者多在发病1周后出现呼吸困难和(或)低氧血症,严重者快速进展为急性呼吸窘迫综合征、脓毒症休克、难以纠正的代谢性酸中毒和出凝血功能障碍等。COVID-19目前尚无特效治疗手段,有学者认为,避免细胞因子风暴可能是治疗COVID-19感染患者的关键。间充质干细胞(mesenchymal stem cells,MSCs)具有强大的免疫调节能力,可能对预防或减弱细胞因子风暴、降低本病的发病率和死亡率具有一定的作用。海南医学院第二附属医院于2020年2月采用脐带间充质干细胞治疗2例新型冠状病毒肺炎患者,取得一定疗效。     

病毒逃逸宿主免疫反应机制的研究进展

先天性免疫反应是宿主抵御病毒感染的第一道防线,也是激活适应性免疫的基础,其在宿主清除病毒的免疫反应中发挥关键作用,成为当前免疫学研究的热点。在先天性免疫反应中,病毒感染细胞后主要通过模式识别受体识别病毒入侵,进而产生干扰素和一系列细胞因子来抵抗病毒入侵或清除病毒;而在适应性免疫中,机体主要通过T细胞和B细胞特异性识别入侵的病毒并将其清除。与此同时,病毒为了能够更好地在宿主细胞中获得生存,进化了多种可逃逸宿主免疫系统的机制。现将主要针对于病毒逃逸宿主免疫反应的一系列机制进行阐述。     

细胞因子在免疫反应和病毒相互作用中的机能

本文介绍了细胞因子信号传导及其产生的调节作用，着重介绍了干扰素以及几个炎性细胞因子的特性、信号传导途径及生物学功能，论述了病毒逃避宿主防御的机制以及细胞因子在免疫反应和病毒相互作用中的机能     

细胞因子在ARDS发病机制中的作用

细胞因子是由多种细胞产生的多肽或低分子糖蛋白,在人体内含量极微,在pg水平就发挥作用。作为特异性免疫反应和非特异性免疫反应的蛋白质,细胞因子以自分泌、旁分泌、或内分泌方式产生,与相应的细胞表面受体结合,在局部或全身发挥复杂的生物学效应,它们的代谢异常和疾病的发生、发展有着密切的关系。有些细胞因子已应用于临床的生物学治疗,具有深远的临床应用价值,故对细胞因子的研究将是一个越来越重要的课题。急性肺损伤(ALI)/急性呼吸窘迫综合征(ARDS)发病机制错综复杂,大量临床和实验室研究证明多种效应细胞释放的炎症介质是造成ARDS的"中心环节",其中TNF-α、IL-1、IL-8、IL-10、CXC趋化因子等细胞因子在ARDS发病中的作用尤为重要。本文就细胞因子在ARDS发病机制中的作用做一综述。     

免疫应答——乙型肝炎病毒治疗中的双刃剑

人体对乙型肝炎病毒(hepatitis B virus,HBV)感染的免疫应答是一个非常复杂的病理过程,一方面免疫反应能有效清除HBV病毒和被病毒感染的肝细胞,对HBV诱发的肝类疾病有较好的治疗作用;另一方面,免疫反应在清除被感染肝细胞的同时,也引起局部炎症反应,从而损伤正常的肝细胞和组织.其中,特异性免疫T细胞及其产生的细胞因子是这一免疫应答过程的重要参与者.侧重总结了在HBV感染治疗中的关键细胞和分子及激活人体免疫应答治疗中的两面性,为调节自身免疫应答治疗HBV,避免应答不当而引发的肝损伤提供理论基础.     

内毒素耐受分子调控机理

多种免疫细胞(如单核细胞等)经低剂量内毒素预处理后可产生对高剂量内毒素的耐受,这种免疫反应称之为内毒素耐受。内毒素耐受是一种由细胞因子信号通路下游负反馈激活的,具有防止炎症持续性伤害的免疫稳态维持机制,主要调控因子包括IL-10细胞因子信号通路、细胞因子信号通路抑制因子和IL-1受体相关激酶。另外,在内毒素耐受免疫反应中存在表观遗传修饰的稳定作用。现就内毒素耐受的主要调控机制及维持机制进行阐述。     

宿主细胞应答病毒感染的细胞信号转导研究新进展

机体如何识别以及清除入侵的病毒一直是分子免疫学研究的重点.早期的研究揭示,病毒的入侵可诱导表达大量的IFNβ,PKR等抗病毒蛋白分子.这些蛋白质分子通过多种方式造成被侵染细胞表现出特殊的状态或迅速凋亡,从而控制病毒的复制和传播,同时诱导产生大量细胞因子和趋化因子等,启动适应性免疫反应的进程.但是,该领域研究的一个重要瓶颈是对于病毒与宿主细胞相互作用的最早期信号事件了解甚微.近几年的研究工作在先天性免疫系统如何识别早期病毒的入侵方面取得了重大进展.TLR3和RIG-I/MDA5细胞信号转导通路,是最近发现的宿主细胞识别与应答病毒的重要调节机制.它们利用不同的细胞信号转导机制诱导先天性免疫反应,主要参与脊椎动物细胞识别和清除RNA病毒的原发抗感染过程,是机体先天免疫系统的一种重要反应机制,直接影响后续适应性免疫系统的作用.就这些细胞信号转导通路在先天性免疫应答中的研究进展做了概述与展望.     

A clinical trial of IL-15 and IL-21 combination therapy for COVID-19 is warranted

Previous studies of SARS-CoV-2 viral infection suggest that both the humoral and cytotoxic arms of the immune system are weak in patients with severe COVID-19 disease when compared to mild disease. A cytokine storm is also induced in severe disease. IL-15 has been shown to support the cytotoxic arm of the immune response. IL-21 has been shown to support both the cytotoxic and humoral arms of the immune response. In addition, in some settings, Il-21 has been shown to actually decrease IL-6 and TNF-alpha production, reducing the inflammatory proteins involved in the cytokine storm. Furthermore, in other settings, the combination of IL-15 and IL-21 has been shown to be more effective than either interleukin alone in promoting an effective immune response. Therefore, a clinical trial that examines the use of the combination of IL-15 and IL-21 for COVID-19 patients is warranted.     

高致病性冠状病毒感染导致宿主免疫应答异常

近二十多年，全球范围内先后爆发了由严重急性呼吸综合征冠状病毒（severe acute respiratory syndrome coronavirus，SARS-CoV）、中东呼吸综合征冠状病毒（middle east respiratory syndrome coronavirus，MERS-CoV）和严重急性呼吸综合征冠状病毒2（severe acute respiratory syndrome coronavirus 2，SARS-CoV-2）3种高致病性冠状病毒导致的疫情。这3种高致病性冠状病毒感染通常伴随着免疫系统功能失调，临床表现有淋巴细胞减少症、细胞因子风暴、急性呼吸系统窘迫综合征，甚至多器官衰竭而导致死亡。揭示高致病性冠状病毒在免疫应答中的作用机制，对于预防与控制冠状病毒感染具有重要意义。本文总结了SARS-CoV、MRES-CoV和SARS-CoV-2的进入机制和受体特征、固有免疫应答和适应性免疫应答失调方面的研究进展，强调了高致病性冠状病毒与宿主免疫应答之间的复杂相互作用，以期为防治冠状病毒感染提供参考。     

Cytokine storm intervention in the early stages of COVID-19 pneumonia

Clinical intervention in patients with corona virus disease 2019 (COVID-19) has demonstrated a strong upregulation of cytokine production in patients who are critically ill with SARS-CoV2-induced pneumonia. In a retrospective study of 41 patients with COVID-19, most patients with SARS-CoV-2 infection developed mild symptoms, whereas some patients later developed aggravated disease symptoms, and eventually passed away because of multiple organ dysfunction syndrome (MODS), as a consequence of a severe cytokine storm. Guidelines for the diagnosis and treatment of SARS-CoV-2 infected pneumonia were first published January 30^th, 2020; these guidelines recommended for the first time that cytokine monitoring should be applied in severely ill patients to reduce pneumonia related mortality. The cytokine storm observed in COVID-19 illness is also an important component of mortality in other viral diseases, including SARS, MERS and influenza. In view of the severe morbidity and mortality of COVID-19 pneumonia, we review the current understanding of treatment of human coronavirus infections from the perspective of a dysregulated cytokine and immune response.     

Potential effects of HMGB1 on viral replication and virus infection-induced inflammatory responses: A promising therapeutic target for virus infection-induced inflammatory diseases

Inflammatory responses, characterized by the overproduction of numerous proinflammatory mediators by immune cells, is essential to protect the host against invading pathogens. Excessive production of proinflammatory cytokines is a key pathogenic factor accounting for severe tissue injury and disease progression during the infection of multiple viruses, which are therefore termed as “cytokine storm”. High mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein released either over virus-infected cells or activated immune cells, may act as a proinflammatory cytokine with a robust capacity to potentiate inflammatory response and disease severity. Moreover, HMGB1 is a host factor that potentially participates in the regulation of viral replication cycles with complicated mechanisms. Currently, HMGB1 is regarded as a promising therapeutic target against virus infection. Here, we provide an overview of the updated studies on how HMGB1 is differentially manipulated by distinct viruses to regulate viral diseases.     

A cytokine super cyclone in COVID-19 patients with risk factors: the therapeutic potential of BCG immunization

The seventh human coronavirus SARS-CoV2 belongs to the cluster of extremely pathogenic coronaviruses including SARS-CoV and MERS-CoV, which can cause fatal lower respiratory tract infection. Likewise, SARS-CoV2 infection can be fatal as the disease advances to pneumonia, followed by acute respiratory distress syndrome (ARDS). The development of lethal clinical symptons is associated with an exaggerated production of inflammatory cytokines, referred to as the cytokine storm, is a consequence of a hyperactivated immune response aginst the infection. In this article, we discuss the pathogenic consequences of the cytokine storm and its relationship with COVID-19 associated risk factors. The increased pro-inflammatory immune status in patients with risk factors (diabetes, hypertension, cardiovascular disease, COPD) exacerbates the Cytokine-storm of COVID-19 into a ‘Cytokine Super Cyclone’. We also evaluate the antiviral immune responses provided by BCG vaccination and the potential role of ‘trained immunity’ in early protection against SARS-CoV2.     

SARS-CoV-2 infection and oxidative stress: Pathophysiological insight into thrombosis and therapeutic opportunities

The current coronavirus disease 2019 (COVID-19) pandemic has presented unprecedented challenges to global health. Although the majority of COVID-19 patients exhibit mild-to-no symptoms, many patients develop severe disease and need immediate hospitalization, with most severe infections associated with a dysregulated immune response attributed to a cytokine storm. Epidemiological studies suggest that overall COVID-19 severity and morbidity correlate with underlying comorbidities, including diabetes, obesity, cardiovascular diseases, and immunosuppressive conditions. Patients with such comorbidities exhibit elevated levels of reactive oxygen species (ROS) and oxidative stress caused by an increased accumulation of angiotensin II and by activation of the NADPH oxidase pathway. Moreover, accumulating evidence suggests that oxidative stress coupled with the cytokine storm contribute to COVID-19 pathogenesis and immunopathogenesis by causing endotheliitis and endothelial cell dysfunction and by activating the blood clotting cascade that results in blood coagulation and microvascular thrombosis. In this review, we survey the mechanisms of how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces oxidative stress and the consequences of this stress on patient health. We further shed light on aspects of the host immunity that are crucial to prevent the disease during the early phase of infection. A better understanding of the disease pathophysiology as well as preventive measures aimed at lowering ROS levels may pave the way to mitigate SARS-CoV-2-induced complications and decrease mortality.     

Pathogenesis and treatment of cytokine storm in COVID-19

COVID-19 is a viral infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that killed a large number of patients around the world. A hyperinflammatory state resulting in a cytokine storm and adult respiratory distress syndrome seems to be the major cause of the death. Many mechanisms have been suggested in the pathogenesis of COVID-19 associated cytokine storm (COVID-CS). Insufficient viral clearance and persistence of a strong cytokine response despite inadequate antiviral immunity seem to be the main mechanisms underlying the pathogenesis. The diagnosis of COVID-19 is based on relatively constant clinical symptoms, clinical findings, laboratory tests, and imaging techniques, while the diagnosis of COVID-CS is a rather dynamic process, based on evolving or newly emerging findings during the clinical course. Management of COVID-19 consists of using antiviral agents to inhibit SARS-CoV-2 replication and treating potential complications including the cytokine storm together with general supportive measures. COVID-CS may be treated using appropriate immunosuppressive and immunomodulatory drugs that reduce the level of inappropriate systemic inflammation, which has the potential to cause organ damage. Currently corticosteroids, IL-6 blockers, or IL-1 blockers are most widely used for treating COVID-CS.     

A critical evaluation of glucocorticoids in the management of severe COVID-19

The viral infection by SARS-CoV-2 has irrevocably altered the life of the majority of human beings, challenging national health systems worldwide, and pushing researchers to rapidly find adequate preventive and treatment strategies. No therapies have been shown effective with the exception of dexamethasone, a glucocorticoid that was recently proved to be the first life-saving drug in this disease. Remarkably, around 20 % of infected people develop a severe form of COVID-19, giving rise to respiratory and multi-organ failures requiring subintensive and intensive care interventions. This phenomenon is due to an excessive immune response that damages pulmonary alveoli, leading to a cytokine and chemokine storm with systemic effects. Indeed glucocorticoids’ role in regulating this immune response is controversial, and they have been used in clinical practice in a variety of countries, even without a previous clear consensus on their evidence-based benefit.     

Interleukin-27 and interferon-gamma are involved in regulation of autoimmune arthritis

Inflammation underlying immune pathology and tissue damage involves an intricate interplay between multiple immunological and biochemical mediators. Cytokines represent the key immune mediators that trigger a cascade of reactions that drive processes such as angiogenesis and proteolytic damage to tissues. IL-17 has now been shown to be a pivotal cytokine in many autoimmune diseases, supplanting the traditional Th1-Th2 paradigm. Also, the dual role of proinflammatory IFN-γ has unraveled new complexities in the cytokine biology of such disorders. A major hurdle in fully understanding the effector pathways in these disorders is the lack of information regarding the temporal kinetics of the cytokines during the course of the disease, as well as the interplay among the key cytokines. Using an experimental model of arthritic inflammation, we demonstrate that the temporal expression of cytokines during the incubation phase is a critical determinant of disease susceptibility. The susceptible rats raised a vigorous IL-17 response early, followed by IFN-γ and IL-27 response in that sequence, whereas the resistant rats displayed an early and concurrent response to these three cytokines. Accordingly, treatment with exogenous IFN-γ/IL-27 successfully controlled arthritic inflammation and inhibited the defined mediators of inflammation, angiogenesis, cell survival, apoptosis, and tissue damage. Furthermore, IFN-γ enhanced IL-27 secretion, revealing a cooperative interplay between the two cytokines. Our results offer a novel immunobiochemical perspective on the pathogenesis of autoimmune arthritis and its therapeutic control.     

Is Toll-like receptor 4 involved in the severity of COVID-19 pathology in patients with cardiometabolic comorbidities?

The severe form of COVID-19 is marked by an abnormal and exacerbated immunological host response favoring to a poor outcome in a significant number of patients, especially those with obesity, diabetes, hypertension, and atherosclerosis. The chronic inflammatory process found in these cardiometabolic comorbidities is marked by the overexpression of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumoral necrosis factor-alpha (TNF-α), which are products of the Toll-Like receptors 4 (TLR4) pathway. The SARS-CoV-2 initially infects cells in the upper respiratory tract and, in some patients, spread very quickly, needing respiratory support and systemically, causing collateral damage in tissues. We hypothesize that this happens because the SARS-CoV-2 spike protein interacts strongly with TLR4, causing an intensely exacerbated immune response in the host's lungs, culminating with the cytokine storm, accumulating secretions and hindering blood oxygenation, along with the immune system attacks the body, leading to multiple organ failure.