Tissue-Specific Immunopathology in Fatal COVID-19.
Tissue-Specific Immunopathology in Fatal COVID-19.
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DOI：
10.1164/rccm.202008-3265oc
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发表时间：
2021-01-15
影响因子：
24.7
通讯作者：
Lucas CD
中科院分区：
文献类型：
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作者：
Dorward DA;Russell CD;Um IH;Elshani M;Armstrong SD;Penrice-Randal R;Millar T;Lerpiniere CEB;Tagliavini G;Hartley CS;Randle NP;Gachanja NN;Potey PMD;Dong X;Anderson AM;Campbell VL;Duguid AJ;Al Qsous W;BouHaidar R;Baillie JK;Dhaliwal K;Wallace WA;Bellamy COC;Prost S;Smith C;Hiscox JA;Harrison DJ;Lucas CD
理由：在危及生命的冠状病毒疾病（COVID-19）中，皮质类固醇可降低死亡率，这表明免疫反应在死亡中起因果作用。这种有害的炎症主要是对严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）的直接反应，还是一种独立的免疫病理过程尚不清楚。目的：了解SARS-CoV-2的器官亲和性和器官特异性炎症反应，以及病毒存在、炎症和器官损伤之间的关系。方法：从11例尸体解剖中获得组织。利用多重PCR和测序技术定位SARS-CoV-2的器官亲和性，通过原位病毒S（刺突）蛋白检测实现细胞分辨率。从37个解剖部位量化炎症的组织学证据，并使用多重免疫荧光技术表征肺部免疫反应。测量结果和主要结果：在致死性COVID-19中发现了多种异常免疫反应，主要涉及肺和网状内皮系统，这些免疫反应与病毒的拓扑关系不明确。炎症和器官功能障碍与组织间或组织内SARS-CoV-2 RNA和蛋白质的组织和细胞分布无关。在肺部发现动脉炎，进一步表征为单核细胞/骨髓丰富的血管炎，并与巨噬细胞/单核细胞谱系细胞流入肺实质一起发生。此外，刻板的异常网状内皮反应，包括过度的反应性浆细胞增多症和铁负载巨噬细胞，在淋巴组织中存在并与病毒分离。结论：组织特异性免疫病理在COVID-19中发生，这意味着免疫介导的、不依赖病毒的免疫病理过程的一个重要组成部分是严重疾病的主要机制。我们的数据强调了新的免疫病理机制，并验证了正在进行和未来的努力，以治疗异常巨噬细胞和浆细胞反应，并促进COVID-19的病原体耐受性。
Rationale: In life-threatening coronavirus disease (COVID-19), corticosteroids reduce mortality, suggesting that immune responses have a causal role in death. Whether this deleterious inflammation is primarily a direct reaction to the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or an independent immunopathologic process is unknown. Objectives: To determine SARS-CoV-2 organotropism and organ-specific inflammatory responses and the relationships among viral presence, inflammation, and organ injury. Methods: Tissue was acquired from 11 detailed postmortem examinations. SARS-CoV-2 organotropism was mapped by using multiplex PCR and sequencing, with cellular resolution achieved by in situ viral S (spike) protein detection. Histologic evidence of inflammation was quantified from 37 anatomic sites, and the pulmonary immune response was characterized by using multiplex immunofluorescence. Measurements and Main Results: Multiple aberrant immune responses in fatal COVID-19 were found, principally involving the lung and reticuloendothelial system, and these were not clearly topologically associated with the virus. Inflammation and organ dysfunction did not map to the tissue and cellular distribution of SARS-CoV-2 RNA and protein between or within tissues. An arteritis was identified in the lung, which was further characterized as a monocyte/myeloid-rich vasculitis, and occurred together with an influx of macrophage/monocyte-lineage cells into the pulmonary parenchyma. In addition, stereotyped abnormal reticuloendothelial responses, including excessive reactive plasmacytosis and iron-laden macrophages, were present and dissociated from viral presence in lymphoid tissues. Conclusions: Tissue-specific immunopathology occurs in COVID-19, implicating a significant component of the immune-mediated, virus-independent immunopathologic process as a primary mechanism in severe disease. Our data highlight novel immunopathologic mechanisms and validate ongoing and future efforts to therapeutically target aberrant macrophage and plasma-cell responses as well as promote pathogen tolerance in COVID-19.