4月9日，中国工程院院士、南开大学校长曹雪涛院士应Nature子刊约稿邀请，在Nature Reviews Immunology《自然—免疫学综述》（IF=44） 在线发表题为：COVID-19: immunopathology and its implications for therapy 《新冠肺炎的免疫病理及其对于治疗的启示》的评述文章。
文章系统总结了SARS-CoV-2产生的免疫学反应及潜在的治疗方法，这对于进一步认清SARS-CoV-2的致病机制提供了很好的参考作用，同时对于更好的控制COVID-19指引了方向。文章署名单一作者：Xuetao cao，在文中，作者通过与钟南山院士“个人交流”备注方式表示:中医药治疗新冠肺炎有临床疗效。
今日，《中国科学报》就该文对曹雪涛院士进行了专访，采访中，曹雪涛院士首次透露了，在和期刊编辑部沟通后，为何在文中采取与钟南山院士“个人交流”的备注方式的细节。详见：
曹雪涛专访 | 新发《自然》子刊评述文章，谈新冠肺炎免疫病理和治疗启示《中国科学报》
《自然—免疫学综述》何时向您提出了此次约稿？约稿的背景和要求是什么？。
曹雪涛：3月16日杂志向我约稿，那时英国的新冠疫情开始受到各方关注。大家在讨论如何应对的过程中，越来越意识到借鉴中国疫情防控措施与经验的重要性。特别是他们陆续看到中国在重症新冠肺炎患者临床治疗方面的报道，这部分重症患者怎么治好的、用了什么方法？学界非常感兴趣。因此，希望我从免疫学的角度向国际同行介绍新冠肺炎的免疫病理特点以及对临床治疗和相关药物研发的启示。
《中国科学报》
有别于之前的综述长文，这篇评述为何仅2页？您想通过这篇评述，陈述什么观点？
曹雪涛：这是一篇简要评述，而不是综述，这个杂志很少刊发评述文体。杂志是希望尽快及时介绍新冠肺炎某一专题方面的相关情况，供生物医学界同行参考。其实，目前很多杂志都开设了新冠肺炎特殊栏目，甚至是投稿的绿色通道。新冠肺炎是全人类面对的共同挑战，因此杂志方面提出要求，希望能够简洁明了，快点写好。具体要求是1500字以内、10篇参考文献。我在写稿的过程中，新冠肺炎相关的新文章接二连三地发表，陆陆续续我写了3000多字，最后只能删减。所以我在评述最后的致谢中说明，由于字数限制，对未能引用的研究成果表示歉意。在这篇评述中集中写了一个主题，即免疫在新冠肺炎的发病和治疗中起什么作用，围绕免疫病理，讨论免疫调节怎么影响新冠肺炎的转归和治疗，从而进一步探索新冠肺炎治疗的新靶标和干预的新途径。
《中国科学报》
评述中，关于中医药治疗新冠肺炎疗效的内容，您引用了个人与钟南山院士交流的观点，并做了标注，这是否有特殊原因？
曹雪涛：这部分内容，虽然在文中就一句话，其实是用精炼的语言，表达了一个态度。中医药确实为抗击新冠肺炎疫情发挥了作用。我和张伯礼院士经常交流，他一直在临床一线应用中医药成果治疗各个阶段的新冠肺炎患者，取得了令人瞩目的临床效果。我与钟南山院士沟通，从他那里获悉，他的团队在体外实验证明中药能抑制新冠病毒复制及其诱导的炎症因子产生的基础上（已发表文章），通过双盲对照试验，在临床上也看到了疗效（即将发表文章）。于是，杂志同意在文中注明中医药治疗新冠肺炎有临床疗效，但当时没有正式发表的临床疗效论文可供引用，经与杂志编辑部沟通，决定采取与钟南山院士“个人交流”的方式。文中以钟南山院士全名的形式引用标注，我想这反映出了钟南山院士作为一位中国临床专家的巨大国际影响力，也体现了中医药在国际学界越来越受到关注。
该评述中引用与钟南山院士交流观点
以下为文章中文翻译和英文原文：
新冠肺炎的免疫病理及其对于治疗的启示
COVID-19是由严重的急性呼吸综合症冠状病毒2（SARS-CoV-2）引起的一种新出现的呼吸系统疾病，最近已成为大流行病。大多数COVID-19患者表现出轻度至中度症状，但约15％进展为严重的肺炎，约5％最终发展为急性呼吸窘迫综合征（ARDS），败血性休克和/或多器官功能衰竭。临床治疗的主要内容包括对症管理和氧气治疗，并为呼吸衰竭患者提供机械通气。尽管正在积极测试包括核苷酸类似物remdesivir在内的几种抗病毒药物，但尚未专门批准将其用于COVID-19。除了直接针对病毒或阻断病毒进入的疫苗开发和方法外，解决感染的免疫病理学问题的治疗也成为主要关注点。
SARS-CoV-2感染可激活先天性和适应性免疫反应。但是，不受控制的炎性先天反应和受损的适应性免疫反应可能导致局部和全身有害的组织损伤。在严重COVID-19的患者中，淋巴细胞减少症是一个常见特征，CD4 + T细胞，CD8 + T细胞，B细胞和自然杀伤（NK）细胞数量急剧减少，以及单核细胞，嗜酸性粒细胞和嗜碱性粒细胞的百分比急剧下降。中性粒细胞计数和中性粒细胞与淋巴细胞之比的增加通常表明疾病严重程度较高，临床预后较差。此外，COVID-19患者的细胞毒性淋巴细胞（包括NK细胞和CD8 + T细胞）上的耗尽标记（例如NKG2A）被上调。在康复或恢复期的患者中，CD4 + T细胞，CD8 + T细胞，B细胞和NK细胞的数量以及细胞毒性淋巴细胞衰竭的标志正常化。此外，可以检测到SARS-CoV-2-特异性抗体。
含有中和抗体的恢复性血浆已用于治疗少数重症患者，初步结果显示，在5名发展为ARDS的COVID-19危重患者中，其临床症状显着改善。通过高通量平台，例如来自康复期患者的B细胞的大规模单细胞RNA测序（富集产生针对SARS-CoV-2刺突蛋白的抗体的B细胞），已可以鉴定SARS -CoV-2特异性中和抗体。
结合基于RT-PCR的检测，对患者SARS-CoV-2特异性IgM和IgG的检测为疾病诊断提供了基础。然而，两项分别基于222例和173例COVID-19的分析的研究报告说，患有严重疾病的患者常常具有更高的IgG反应和更高的总抗体滴度，这与更差的预后相关。这暗示了SARS-CoV-2感染可能的抗体依赖性增强。
大多数患有严重COVID-19的患者表现出血清促炎细胞因子水平显着升高，包括IL-6和IL-1β以及IL-2，IL-8，IL-17，G-CSF，GM-CSF，IP10 ，MCP1，MIP1α（也称为CCL3）和TNF，特征为细胞因子风暴。另外，发现C反应蛋白和D-二聚体异常高。高水平的促炎性细胞因子可能导致心脏，肝脏和肾脏的休克和组织损伤，以及呼吸衰竭或多器官衰竭。它们还介导广泛的肺部病理，导致嗜中性粒细胞和巨噬细胞大量浸润，弥漫性肺泡损伤。
许多研究已经尝试了抑制炎症反应的策略。在患有严重肺炎和ARDS的严重COVID-19患者中，发现IL-6水平升高是不良预后的稳定指标。一项使用IL-6受体靶向单克隆抗体（mAb）托珠单抗的临床试验（ChiCTR2000029765）：报告了在中国安徽治疗的21例严重COVID-19患者的发烧快速控制和呼吸功能的改善。所有患者，包括两名重病患者，均已康复并已出院。这项令人鼓舞的临床试验表明，针对其他促炎细胞因子的中和单克隆抗体也可能有用，其潜在靶标包括IL-1，IL-17及其各自的受体。此外，其下游信号传导成分的小分子抑制剂有望阻止细胞因子风暴相关的免疫病理学。希望这些方法将被批准用于临床试验，以使患者受益。
缓解COVID-19相关免疫病理的另一种方法涉及间充质干细胞（MSC），其发挥抗炎和抗凋亡作用，可以修复肺上皮细胞损伤并促进肺泡液清除。受到临床前和临床研究的鼓舞，这些研究证实了它们在非COVID-19相关疾病中的安全性和有效性，目前已在中国启动了以MSC为基础治疗重症COVID-19的临床试验，目前正在进行两项试验。为了进一步帮助我们对抗COVID-19，需要为罹患ARDS或多器官功能衰竭的高风险患者识别预后生物标志物。年龄（50岁以上）已成为严重疾病的一个独立危险因素，这引发了人们对在该人群中产生有效疫苗诱导有效细胞和体液反应的可行性的担忧。此外，似乎患有COVID-19和高血压或糖尿病的患者更容易患上严重疾病。描述这些慢性疾病导致疾病恶化的机制，以及更好地理解SARS-COV-2免疫逃逸机制，可能为严重病例的临床治疗提供线索。至关重要的是，在全球范围内推荐成功的针对严重病例的标准化治疗方案，以应对COVID-19大流行。抗炎药和抗病毒药的联合使用可能比单独使用任何一种方式更有效。基于抑制SARS-CoV-2复制并阻止SARS-CoV-2感染诱导的促炎性细胞因子产生的体外证据，中药已显示出临床疗效（钟南山，个人交流）。到目前为止，可能会影响治疗结果的另一项尚未充分研究的致病因素涉及压力诱发的神经内分泌-免疫串扰疾病。众所周知，在对病毒感染的天然免疫反应的背景下释放的细胞因子可以诱导神经内分泌系统释放糖皮质激素和其他肽，从而削弱免疫反应。已从呼吸道，粪便和尿液样本中分离出传染性SARS-CoV-2病毒颗粒。SARS-CoV-2是否可以感染中枢神经系统，促进炎症诱导的病理性神经内分泌介质的释放，从而影响呼吸功能和ARDS发病机理，值得进一步研究。COVID-19: immunopathology and its implications for therapy
Severe coronavirus disease (COVID-19) is characterized by pneumonia, lymphopenia, exhausted lymphocytes and a cytokine storm. Significant antibody production is observed; however, whether this is protective or pathogenic remains to be determined. Defining the immunopathological changes in patients with COVID-19 provides potential targets for drug discovery and is important for clinical management.
Coronavirus disease (COVID-19), a newly emerged respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has recently become pandemic. Most patients with COVID-19 exhibit mild to moderate symptoms, but approximately 15% progress to severe pneumonia and about 5% eventually develop acute respiratory distress syndrome (ARDS), septic shock and/or multiple organ failure1,2. The mainstay of clinical treatment consists of symptomatic management and oxygen therapy, with mechanical ventilation for patients with respiratory failure. Although several antiviral drugs, including the nucleotide analogue remdesivir, are being actively tested, none has been specifically approved for COVID-19. In addition to vaccine development and approaches that directly target the virus or block viral entry, treatments that address the immunopathology of the infection have become a major focus.
SARS-CoV-2 infection can activate innate and adaptive immune responses. However, uncontrolled inflammatory innate responses and impaired adaptive immune responses may lead to harmful tissue damage, both locally and systemically. In patients with severe COVID-19, but not in patients with mild disease, lymphopenia is a common feature, with drastically reduced numbers of CD4+T cells, CD8+T cells, B cells and natural killer (NK) cells1,2,3,4, as well as a reduced percentage of monocytes, eosinophils and basophils3,5. An increase in neutrophil count and in the neutrophil-to-lymphocyte ratio usually indicates higher disease severity and poor clinical outcome5. In addition, exhaustion markers, such as NKG2A, on cytotoxic lymphocytes, including NK cells and CD8+T cells, are upregulated in patients with COVID-19. In patients who have recovered or are convalescent, the numbers of CD4+T cells, CD8+T cells, B cells and NK cells and the markers of exhaustion on cytotoxic lymphocytes normalize6,7. Moreover, SARS-CoV-2-specific antibodies can be detected.
Convalescent plasma containing neutralizing antibodies has been used to treat a small number of patients with severe disease, and preliminary results show clinical improvement in 5 of 5 critically ill patients with COVID-19 who developed ARDS8. High-throughput platforms, such as the large-scale single-cell RNA sequencing of B cells (enriched for B cells that produce antibodies directed at the SARS-CoV-2 spike glycoprotein) from patients who are convalescent, have allowed the identification of SARS-CoV-2-specific neutralizing antibodies.
The detection of SARS-CoV-2-specific IgM and IgG in patients provided the basis for disease diagnosis, in conjunction with RT-PCR-based tests. However, two studies, based on the analysis of 222 and 173 patients with COVID-19, respectively, reported that patients with severe disease frequently had an increased IgGresponse and a higher titre of total antibodies, which was associated with worse outcome5,9. This was suggestive ofpossible antibody-dependent enhancement (ADE)of SARS-CoV-2 infection. The immunopathological effectsof ADE have been observed in various viral infections, characterized as antibody-mediated enhancement of viral entry and induction of a severe inflammatory response. Worryingly, it was shown that a neutralizing monoclonal antibody targeting the receptor-binding domain of the spike protein of the related Middle East respiratory syndrome (MERS) virus can enhance viral entry. A potential pathogenic effect of antibodies targeted at SARS-CoV-2 would be of major concern for vaccine development and antibody-based therapies. Additional independent large-cohort studies are needed to substantiate or dismiss this possibility.
Most patients with severe COVID-19 exhibit substantially elevated serum levels of pro-inflammatory cytokines including IL-6 and IL-1β, as well as IL-2, IL-8, IL-17, G-CSF, GM-CSF, IP10, MCP1, MIP1α (also known as CCL3) and TNF, characterized as cytokine storm1,2,3,4. Also, C-reactive protein and D-dimer are found to be abnormally high. High levels of pro-inflammatory cytokines may lead to shock and tissue damage in the heart, liver and kidney, as well as respiratory failure or multiple organ failure. They also mediate extensive pulmonary pathology, leading to massive infiltration of neutrophils and macrophages, diffuse alveolar damage with the formation of hyaline membranes and a diffuse thickening of the alveolar wall. Spleen atrophy and lymph node necrosis were also observed, indicative of immune-mediated damage in deceased patients.
A number of studies have trialled strategies to dampen inflammatory responses. Elevated levels of IL-6 were found to be a stable indicator of poor outcome in patients with severe COVID-19 with pneumonia and ARDS. One clinical trial (ChiCTR2000029765), using the IL-6 receptor-targeted monoclonal antibody (mAb) tocilizumab, reported quick control of fever and an improvement of respiratory function in 21 patients with severe COVID-19 treated in Anhui, China. All patients, including two who were critically ill, have recovered and have been discharged from hospital. The efficacy of tocilizumab in treating patients with COVID-19 who develop ARDS needs to be further assessed in larger randomized controlled trials. This encouraging clinical trial indicates that neutralizing mAbs against other pro-inflammatory cytokines may also be of use, with potential targets including IL-1, IL-17 and their respective receptors. Moreover, small-molecule inhibitors of their downstream signalling components may hold promise for blocking cytokine storm-related immunopathology. In addition to the cytokine-based pathology in patients with severe COVID-19, complement activation has also been observed, indicating that complement inhibitors, if used at an early stage of the infection, may attenuate the inflammatory damage. Hopefully these approaches will be approved into clinical trials to benefit the patients.
Another approach to alleviate COVID-19-related immunopathology involves mesenchymal stem cells (MSCs), which exert anti-inflammatory and anti-apoptotic effects, can repair pulmonary epithelial cell damage and promote alveolar fluid clearance. Encouraged by preclinical and clinical studies that confirmed their safety and efficacy in non-COVID-19-related pathologies, clinical trials of MSC-based therapy in patients with severe COVID-19 have been initiated in China and two trials are currently ongoing.
To further help our fight against COVID-19, prognostic biomarkers need to be identified for patients at high risk of developing ARDS or multiple organ failure. Age (above 50 years) has emerged as one independent risk factor for severe disease, raising concerns about the feasibility of generating a potent vaccine to induce efficient cellular and humoral responses in this population. In addition, it appears that patients with COVID-19 and hypertension or diabetes are more likely to develop severe disease. Delineating the mechanisms behind these chronic diseases for worsening disease outcome, as well as a better understanding of SARS-COV-2 immune-escape mechanisms, may provide clues for the clinical management of the severe cases.
It is of utmost importance that successful standardized treatment protocols for severe cases are recommended globally to fight the COVID-19 pandemic. The combined use of anti-inflammatory and antiviral drugs may be more effective than using either modality alone.Based on in vitro evidence for inhibiting SARS-CoV-2 replication and blocking SARS-CoV-2 infection-induced pro-inflammatory cytokine production10, a Chinese traditional medicine has demonstrated clinical efficacy (Nanshan Zhong, personal communication).
Another, so-far under-investigated pathogenic factor that may affect therapeutic outcome involves stress-induced disorders of the neuroendocrine–immune crosstalk. It is well known that cytokines released in the context of innate immune responses to viral infections can induce the neuroendocrine system to release glucocorticoids and other peptides, which can impair immune responses. Infectious SARS-CoV-2 viral particles have been isolated from respiratory, faecal and urine samples. Whether SARS-CoV-2 can infect the central nervous system, facilitating the release of inflammation-induced pathological neuroendocrine mediators that impact on respiratory function and ARDS pathogenesis, warrants investigation.
References1.Huang, C. et al. Clinical features of patients infected with novel coronavirus in Wuhan, China. Lancet 395, 497–506 ().2.Xu, Z. et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med. 8, 420–422 ().3.Qin, C. et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin. Infect. Dis. /10.1093/cid/ciaa248 ().4.Shi, Y. et al. Immunopathological characteristics of coronavirus disease cases in Guangzhou, China. Preprint at medRxiv /10.1101/.03.12.4736 ().5.Zhang, B. et al. Immune phenotyping based on neutrophil-to-lymphocyte ratio and IgG predicts disease severity and outcome for patients with COVID-19. Preprint at medRxiv /10.1101/.03.12.5048 ().6.Chen, X. et al. Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients. Preprint at medRxiv /10.1101/.03.03.0437 ().7.Zheng, M. et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell. Mol. Immunol. /10.1038/s41423-020-0402-2 ().8.Shen, C. et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA /10.1001/jama..4783 ().9.Zhao, J. et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease . Clin. Infect. Dis. /10.1093/cid/ciaa344 ().10.Runfeng, L. et al. Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2). Pharmacol. Res. /10.1016/j.phrs..104761 ().
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本文综合自中国科学报，iNature，仅用于学术分享。
