冠状病毒对天然免疫的抑制作用

由严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2, SARS-CoV-2)引起的新型冠状病毒肺炎(corona virus disease 2019, COVID-19),至今仍在全球范围内流行。21世纪以来,数次冠状病毒感染疫情促使人类更加重视冠状病毒,尤其是COVID-19疫情的暴发与大流行,更将新冠病毒提升为全球的研究重点。免疫反应与病毒的感染、清除以及病理损伤等密切相关。天然免疫是机体防御体系的重要组成部分和首道防线,在病毒感染早期对于抑制病毒的复制和扩散具有至关重要的作用,并且在获得性免疫的启动及后续的发展中也发挥着关键的调控功能。研究表明,免疫逃逸是冠状病毒的重要致病机制,冠状病毒能够通过多种方式抑制宿主的天然免疫应答。现对SARS-CoV-2等主要的冠状病毒抑制天然免疫的分子机制作一概述,以期为抗冠状病毒感染的疫苗及治疗性药物的研发提供帮助。     

磷酸氯喹在新型冠状病毒感染性肺炎治疗中合理应用

抗病毒治疗及有效的机体免疫应答与新型冠状病毒肺炎的病情进展有重要关系。基于对新型冠状病毒有良好的抑制作用,磷酸氯喹被列入《新型冠状病毒感染肺炎诊疗方案》。本文根据现有证据,探讨其在新型冠状病毒感染治疗中的作用机制和潜在风险,为合理应用提出建议,以期为新型冠状病毒肺炎相关临床决策提供参考,提高临床治疗效果。     

应激颗粒在冠状病毒复制中的作用及机制

近年来多种冠状病毒感染后引发患者严重的呼吸道疾病,造成危害人类健康的严重公共卫生事件。新型冠状病毒（SARS-CoV-2）暴发以来,大量研究使得人们对冠状病毒与宿主相互作用机制有更多的了解,其中关于病毒感染后应激颗粒的形成和抗病毒作用也做了大量研究。病毒的RNA和蛋白可以激活宿主细胞内蛋白激酶R(Protein kinase R,PKR)及其下游信号,刺激应激颗粒（Stress granules,SGs）的形成,进而降低病毒在宿主细胞内所需蛋白的翻译水平,抑制病毒复制。然而冠状病毒与宿主长期博弈过程中也衍生出对抗细胞SGs的相应机制,比如利用蛋白与SGs相互作用,来抑制SGs的形成和解聚,逃逸细胞对病毒的抑制作用,保证病毒稳定复制,其中新型冠状病毒就是典型的例子。因此SGs的诱导为抗冠状病毒可能提供一个新型治疗策略。本文对冠状病毒感染抵抗细胞应激颗粒的形成促进其解聚的分子机制进行综述。     

间充质干细胞治疗新型冠状病毒肺炎的研究进展与应用前景

当前新型冠状病毒肺炎疾病已在全球大规模蔓延,严重危害人类的健康。新病毒感染性强并且感染后重症患者病死率较高,目前尚无有效的特异性治疗药物,因此亟待寻找安全有效的治疗方法。间充质干细胞(Mesenchymal stem cells,MSCs)具有强大的免疫调节和组织损伤修复与再生的生物学功能,因此作为一种干细胞疗法有潜力降低新冠肺炎重症患者的组织损伤和死亡率。目前,我国和国外多家研究机构已启动多项MSCs治疗新型冠状病毒肺炎的相关临床研究项目,已初步证实该疗法的安全性和有效性,因此具有非常良好的临床治疗前景。     

通过SARS和MERS对COVID-19的最新认识

自新型冠状病毒肺炎疫情暴发以来,有关新型冠状病毒的研究非常多,且借鉴对冠状病毒的现有研究,2019新型冠状病毒的感染机理也逐步认识。对于这种新型冠状病毒引起的肺炎的诊疗措施及相关药物的开发也已经开展,通过对其感染过程及受体的研究,各种抗病毒类药物再一次引起我们的兴趣。基于此前出现的SARS冠状病毒、MERS冠状病毒,以及现今的2019新型冠状病毒三种感染人的冠状病毒,本综述主要论述冠状病毒的发展进化史、传播源及传播途径、病毒的感染与复制、预防措施以及诊疗手段。     

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。     

重症新型冠状病毒肺炎患者遗传易感性研究进展

新型冠状病毒肺炎是由新型冠状病毒感染引起的全球大流行疾病。患者呈现出无症状感染、轻症到(危)重症不同严重程度的临床表现。部分重症患者因发生细胞因子风暴而出现多器官功能衰竭并最终导致死亡。除性别、年龄、基础疾病(如高血压、糖尿病)等增加重型感染风险外,宿主先天遗传缺陷也被认为与疾病严重程度(包括细胞因子风暴的发生)密切相关。在重症患者中,相继发现与病毒识别、杀伤等相关的关键基因(如TLR7、UNC13D等)先天遗传变异。本文主要总结了宿主抗病毒免疫应答机制及与新型冠状病毒感染严重程度相关的先天变异基因,以期为新型冠状病毒肺炎的早期干预和分层治疗提供遗传学依据。     

间充质干细胞在新型冠状病毒肺炎治疗中的研究现状

新型冠状病毒肺炎(COVID-19)由新型冠状病毒(SARS-CoV-2)导致,可发生严重肺部损伤甚至死亡,目前为止仍在全球范围内广泛蔓延。SARS-CoV-2感染依赖于血管紧张素转换酶2(ACE2)和Ⅱ型跨膜丝氨酸蛋白酶,可导致机体免疫紊乱,促发炎症风暴从而损伤靶器官。COVID-19目前尚无特效药物,间充质干细胞(MSCs)具有组织修复和免疫调节等功能,而且在流感病毒相关性肺炎及其他肺疾病中有一定疗效,因此可能是治疗COVID-19潜在有效药物。目前部分研究也显示出积极的治疗效果,而具体的疗效仍需进一步的临床研究来验证。     

SARS-CoV-2入侵细胞相关分子结构与机制的研究进展

新型冠状病毒肺炎(corona virus disease 2019, COVID-19)疫情的迅速发展与其病原体新型冠状病毒(severeacuterespiratorysyndromecoronavirus2,SARS-Co V-2)具有的高传播、高感染能力关系密切。这是一种新型β属冠状病毒,为了探究其高传染性的原因,并为治疗药物和防控疫苗的开发提供理论依据,研究人员迅速展开了针对新型冠状病毒入侵细胞分子机制的研究,并取得了较多进展。该文以新型冠状病毒表面的刺突糖蛋白(spike glycoprotein, S protein)和宿主细胞表面的血管紧张素转换酶2 (angiotensin converting enzyme2, ACE2)的相互作用为重点,介绍了此病毒入侵细胞的分子结构与机制的最新研究进展,总结了病毒入侵环节中潜在的药物靶点,并对新型冠状病毒的研究提出了展望。     

间充质干细胞治疗新冠肺炎的科学性和可行性探讨

自新型冠状病毒肺炎(Coronavirus disease 2019, COVID-19)(以下简称"新冠肺炎")暴发以来,国内外研究团队积极探索可行的治疗方案,但截至目前,尚无针对新冠肺炎的特效治疗药物.间充质干细胞(mesenchymal stem cells, MSCs)是一类多潜能组织干细胞,具有免疫调节和组织修复功能.应用MSCs治疗急性肺损伤、重症肺炎、急性呼吸窘迫综合征的临床研究显示, MSCs输注有良好的安全性和有效性.目前,国内外已有多项利用MSCs治疗COVID-19的临床试验正式注册,正在开展临床研究.结合COVID-19的病理特征和目前研究情况,本文主要探讨MSCs治疗新冠肺炎的科学性和可行性,以期为正确把握和评判MSCs在COVID-19的潜在治疗价值提供有益的参考信息.     

免疫反应动力学的几个数学模型

免疫系统对抗原刺激的应答过程非常复杂,由抗原刺激导致抗体产生的现象,可借助数学模型的研究获得有意义的结果。本文讨论有关抗体产生与免疫反应的动力学的问题,介绍有关的数学模型,并根据近斯免疫学研究的进展分析了若干模型。     

黏膜抗体在疫苗免疫效力评价中的前景

简单介绍目前疫苗效力检验的方法、黏膜抗体的功能及其在实验室疫苗效果效力评价中的应用,提出了黏膜抗体作为疫苗免疫效力试验的替代指标或免疫监测的主要抗体的建议。     

Relationship Between Immune Cell Phenotypes and Pig Growth in a Commercial Farm

The objective of this study was to evaluate the relationship between the level and function of circulating immune cells with average daily gain, live and carcass measurements, feed intake, and feed conversion. Production performance was monitored throughout the pig's lifetime. Pigs were moved in weekly batches through the nursery and growing/finishing rooms at specific target weights. Animals were individually weighed at birth and at weaning, and then every two weeks while they were “on test” until they were “off test” and sent to the slaughterhouse. At six to seven weeks of age, the pigs were bled in the nursery. The percentage of immune cell subsets and lymphocyte proliferation was estimated using swine monoclonal antibodies and flow cytometric analysis. The predictive effect of the immune cell subset markers and lymphocyte proliferation on production traits was statistically analyzed. The results indicated that the proportion of several peripheral cell subsets, including CD16+, CD2+/CD16+, and CD8+ lymphocytes, appear to predict growth during the entire productive life of the pig. Larger percentages of lymphocytes expressing CD16+ CD2+/CD16+, and CD8+receptors in blood resulted in a reduction in average daily gain. In addition, high percentages of SLA-DQ+ cells were associated with better carcass weight and feed conversion. The CD16+, CD2+/CD16+, CD8+, and SLA-DQ± cell subsets appear to be important biomarkers involved with the inherent ability of the pig to efficiently grow and produce better carcass weight in representative commercial environments.     

增强DNA疫苗免疫应答的新进展

DNA疫苗为编码抗原蛋白的真核表达载体,注入体内后在原位表达所编码的抗原并诱导免疫应答,在预防感染、治疗自身免疫性疾病、过敏性疾病和肿瘤等疫病中有着很好的应用前景。但与灭活疫苗相比,其免疫效价还比较低。有多种策略能够增强或调节DNA疫苗诱导的免疫应答,其中,作为外源基因载体的质粒的组成及插入的有关基因均可直接或间接地影响免疫反应的效果,在构建DNA疫苗质粒时,加入细胞因子、融合信号、泛素等基因以及ISS序列,另外还可以通过设计一些对抗原提成细胞有影响的分子共注射,以及加入转移分子,都可以明显增强DNA疫苗的免疫效果,从而有利于研制更有效的DNA疫苗。     

Modeling regulation mechanisms in the immune system

We develop a mathematical framework for modeling regulatory mechanisms in the immune system. The model describes dynamics of key components of the immune network within two compartments: lymph node and tissue. We demonstrate using numerical simulations that our system can eliminate virus-infected cells, which are characterized by a tendency to increase without control (in absence of an immune response), while tolerating normal cells, which are characterized by a tendency to approach a stable equilibrium population. We experiment with different combinations of T cell reactivities that lead to effective systems and conclude that slightly self-reactive T cells can exist within the immune system and are controlled by regulatory cells. We observe that CD8+ T cell dynamics has two phases. In the first phase, CD8+ cells remain sequestered within the lymph node during a period of proliferation. In the second phase, the CD8+ population emigrates to the tissue and destroys its target population. We also conclude that a self-tolerant system must have a mechanism of central tolerance to ensure that self-reactive T cells are not too self-reactive. Furthermore, the effectiveness of a system depends on a balance between the reactivities of the effector and regulatory T cell populations, where the effectors are slightly more reactive than the regulatory cells.     

Genomic instability,inflammatory signaling and response to cancer immunotherapy

Genomic and chromosomal instability are hallmarks of cancer and shape the genomic composition of cancer cells, thereby determining their behavior and response to treatment. Various genetic and epigenetic alterations in cancer have been linked to genomic instability, including DNA repair defects, oncogene-induced replication stress, and spindle assembly checkpoint malfunction. A consequence of genomic and chromosomal instability is the leakage of DNA from the nucleus into the cytoplasm, either directly or through the formation and subsequent rupture of micronuclei. Cytoplasmic DNA subsequently activates cytoplasmic DNA sensors, triggering downstream pathways, including a type I interferon response. This inflammatory signaling has pleiotropic effects, including enhanced anti-tumor immunity and potentially results in sensitization of cancer cells to immune checkpoint inhibitors. However, cancers frequently evolve mechanisms to avoid immune clearance, including suppression of inflammatory signaling. In this review, we summarize inflammatory signaling pathways induced by various sources of genomic instability, adaptation mechanisms that suppress inflammatory signaling, and implications for cancer immunotherapy.     

肾透明细胞癌中免疫检查点相关的免疫逃逸机制的研究进展

摘要：近年来,免疫治疗在晚期肾透明细胞癌的治疗中异军突起,使人们对于肾癌治疗有了全新的认识。肿瘤免疫治疗药物是通过抑制免疫检查点从而抑制肿瘤细胞免疫逃逸,使免疫细胞可以杀伤肿瘤细胞来发挥治疗作用。因此,了解肾透明细胞癌中免疫检查点相关免疫逃逸机制对于制定有效的治疗策略以及开发新的免疫治疗药物至关重要。本文对目前肾透明细胞癌中主要的免疫检查点（PD-1/PD-L1、CTLA-4、B7-H4、LAG-3、TIM-3和HLA-G）相关的免疫逃逸机制进行综述。     

Type 2 diabetes mellitus coincident with pulmonary or latent tuberculosis results in modulation of adipocytokines

Type 2 diabetes mellitus (T2DM) is recognized as major risk factor for the progress of active pulmonary tuberculosis (PTB), although the mechanistic link between diabetes and tuberculosis remains poorly characterized. Moreover, the influence of poorly controlled diabetes on the baseline levels of adipocytokines in the context of tuberculosis has not been explored in detail. To characterize the influence of coexistent DM on adipocytokine levels in pulmonary or latent TB (LTB), we examined circulating levels of adipocytokines in the plasma of individuals with PTB–DM or LTB–DM and compared them with those without DM (PTB or LTB). PTB–DM or LTB–DM is characterized by diminished circulating levels of adiponectin and adipsin and/or heightened circulating levels of leptin, visfatin and PAI-1. In addition, adiponectin and adipsin exhibit a significant negative correlation, whereas leptin, visfatin and PAI-1 display a significant positive correlation with HbA1C levels and random blood glucose levels. Therefore, our data reveal that PTB–DM or LTB–DM is characterized by alterations in the systemic levels of adipocytokines, indicating that altered adipose tissue inflammation underlying Type 2 diabetes potentially contributes to pathogenesis of TB disease.     

Effective immunotherapy against cancer

During the last decade, the breakthroughs in understanding of the molecular mechanisms responsible for immune activation and the advent of recombinant DNA technologies have changed the view on immunotherapy from a dream scenario to becoming a clinical reality. It is now clear that both cellular immunity comprising T and NK cells, as well as strategies based on antibodies, can provide strong antitumoral effects, and evidence is emerging that these strategies may also cure patients with previously incurable cancers. However, there are still a number of issues that remain unresolved. Progress in immunotherapy against cancer requires a combination of new, improved clinical protocols and strategies for overcoming mechanisms of immune escape and tumor-induced immune suppression. This review discusses some of the salient issues that still need to be resolved, focusing on the role of oxidative stress and the use of antioxidants to alleviate the immune hyporesponsiveness induced by reactive oxygen species (ROS).Abbreviations HLA Human leukocyte antigen - KIR Killer cell immunoglobulin-like receptor - NKR Natural killer cell receptor - ROS Reactive oxygen species - TAA Tumor-associated antigenThis work is part of the Symposium in Writing Tumor escape from the immune response, published in vol 53.     

人FGF-1对免疫系统的影响

酸性成纤维细胞生长因子 (acidfibroblastgrowthfactor,aFGF或FGF-1 )是成纤维细胞生长因子家族成员之一 ,是一种重要的生长因子。人FGF 1 (FGF-1 )是一个 1 7～ 1 8kDa的非糖基化多肽 ,三胚层来源的细胞都可以表达。FGF-1的生物学效应非常广泛 ,在组织和器官发育、血管发生、血细胞生成、肿瘤发生、伤口愈合等方面发挥重要的作用。FGF-1对人体的免疫系统也有重要的影响 ,能提高多种刺激诱导的T细胞增殖、凋亡及细胞因子的产生。主要概述了FGF-1的生物学效应、对免疫系统的影响及其潜在的临床应用价值。