Complement Alternative and Mannose-Binding Lectin Pathway Activation Is Associated With COVID-19 Mortality.
Complement Alternative and Mannose-Binding Lectin Pathway Activation Is Associated With COVID-19 Mortality.
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DOI：
10.3389/fimmu.2021.742446
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发表时间：
2021
影响因子：
7.3
通讯作者：
Cesbron JY
中科院分区：
文献类型：
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作者：
Defendi F;Leroy C;Epaulard O;Clavarino G;Vilotitch A;Le Marechal M;Jacob MC;Raskovalova T;Pernollet M;Le Gouellec A;Bosson JL;Poignard P;Roustit M;Thielens N;Dumestre-Pérard C;Cesbron JY
SARS-CoV-2感染引发过度的免疫反应，导致促炎细胞因子水平升高、内皮损伤和血管内凝血功能障碍。补体系统（CS）的激活参与了这种高炎症反应。然而，目前尚不清楚哪种激活途径（经典、替代或凝集素途径）引导了导致危重疾病的效应机制。为了更好地了解疾病严重程度的免疫相关性，我们分析了2020年4月1日至30日期间在格勒诺布尔阿尔卑斯大学医院住院的COVID-19患者样本中的CS激活途径和成分，以及它们与临床结果的关系。我们对74例经rt - pcr证实的COVID-19住院患者进行了回顾性、单中心研究队列。在住院期间测量患者样本中经典、替代和甘露糖结合凝集素（MBL）途径的功能活性以及单个组分C1q、C4、C3、C5、因子B和MBL的抗原水平。采用Ward方法进行分层聚类，以识别具有相似补体标记特征的患者群。年龄也被纳入模型。然后，将这些聚类与患者的临床特征进行比较：重症监护病房（ICU）入院率、皮质激素治疗、需氧量和死亡率。根据补体参数确定了4个聚类。其中，两组表现出显著的特征：在一组（n = 15）中，患者表现出替代和凝集素途径的激活，MBL、C4、C3、因子B和C5的抗原水平较低；该组患者死亡比例较高（27%），需要氧气支持（80%）或ICU护理（53%）。相比之下，第二簇（n = 19）呈现出具有高经典途径活性和补体成分抗原水平的炎症谱；需要ICU护理的患者比例较低（26%），本组无患者死亡。这些发现支持在严重的COVID-19中替代补体途径和MBL补体途径的显著激活，但补体参与的范围似乎是异质性的，需要更大规模的研究。
The SARS-CoV-2 infection triggers excessive immune response resulting in increased levels of pro-inflammatory cytokines, endothelial injury, and intravascular coagulopathy. The complement system (CS) activation participates to this hyperinflammatory response. However, it is still unclear which activation pathways (classical, alternative, or lectin pathway) pilots the effector mechanisms that contribute to critical illness. To better understand the immune correlates of disease severity, we performed an analysis of CS activation pathways and components in samples collected from COVID-19 patients hospitalized in Grenoble Alpes University Hospital between 1 and 30 April 2020 and of their relationship with the clinical outcomes. We conducted a retrospective, single-center study cohort in 74 hospitalized patients with RT-PCR-proven COVID-19. The functional activities of classical, alternative, and mannose-binding lectin (MBL) pathways and the antigenic levels of the individual components C1q, C4, C3, C5, Factor B, and MBL were measured in patients’ samples during hospital admission. Hierarchical clustering with the Ward method was performed in order to identify clusters of patients with similar characteristics of complement markers. Age was included in the model. Then, the clusters were compared with the patient clinical features: rate of intensive care unit (ICU) admission, corticoid treatment, oxygen requirement, and mortality. Four clusters were identified according to complement parameters. Among them, two clusters revealed remarkable profiles: in one cluster (n = 15), patients exhibited activation of alternative and lectin pathways and low antigenic levels of MBL, C4, C3, Factor B, and C5 compared to all the other clusters; this cluster had the higher proportion of patients who died (27%) and required oxygen support (80%) or ICU care (53%). In contrast, the second cluster (n = 19) presented inflammatory profile with high classical pathway activity and antigenic levels of complement components; a low proportion of patients required ICU care (26%) and no patient died in this group. These findings argue in favor of prominent activation of the alternative and MBL complement pathways in severe COVID-19, but the spectrum of complement involvement seems to be heterogeneous requiring larger studies.