Garvan Institute of Medical Research, Darlinghurst.
St Vincent's Clinical School, UNSW Sydney, Randwick, New South Wales, Australia.
Curr Opin Allergy Clin Immunol. 2021 Dec 1;21(6):515-524. doi: 10.1097/ACI.0000000000000786.
The severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV2)/COVID-19 pandemic has reminded us of the fundamental and nonredundant role played by the innate and adaptive immune systems in host defense against emerging pathogens. The study of rare 'experiments of nature' in the setting of inborn errors of immunity (IEI) caused by monogenic germline variants has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. This review will provide an overview of the discoveries obtained from investigating severe COVID-19 in patients with defined IEI or otherwise healthy individuals.
Genetic, serological and cohort studies have provided key findings regarding host defense against SARS-CoV2 infection, and mechanisms of disease pathogenesis. Remarkably, the risk factors, severity of disease, and case fatality rate following SARS-CoV2 infection in patients with IEI were not too dissimilar to that observed for the general population. However, the type I interferon (IFN) signaling pathway - activated in innate immune cells in response to viral sensing - is critical for anti-SARS-CoV2 immunity. Indeed, genetic variants or autoAbs affecting type I IFN function account for up to 20% of all cases of life-threatening COVID-19.
The analysis of rare cases of severe COVID-19, coupled with assessing the impact of SARS-CoV2 infection in individuals with previously diagnosed IEI, has revealed fundamental aspects of human immunology, disease pathogenesis and immunopathology in the context of exposure to and infection with a novel pathogen. These findings can be leveraged to improve therapies for treating for emerging and established infectious diseases.
综述目的：严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）/COVID-19 大流行提醒我们，固有免疫和适应性免疫系统在宿主防御新兴病原体方面发挥着基本且不可替代的作用。对由单基因种系变异引起的先天性免疫缺陷（ID）中罕见的“自然实验”的研究，揭示了针对传染病进行免疫介导保护的分子和细胞要求的关键见解。这篇综述将概述在患有明确 IDI 或其他健康个体中研究严重 COVID-19 时获得的发现。
最新发现：遗传、血清学和队列研究为宿主防御 SARS-CoV-2 感染以及疾病发病机制的机制提供了关键发现。值得注意的是，IDI 患者 SARS-CoV-2 感染的危险因素、疾病严重程度和病死率与普通人群观察到的没有太大区别。然而，I 型干扰素（IFN）信号通路 - 在先天免疫细胞中对病毒感应的激活 - 对抗 SARS-CoV-2 免疫至关重要。事实上，影响 I 型 IFN 功能的遗传变异或自身抗体占所有危及生命的 COVID-19 病例的 20%。
总结：对严重 COVID-19 的罕见病例进行分析，并评估 SARS-CoV-2 感染对先前诊断为 IDI 的个体的影响，揭示了人类免疫学、疾病发病机制和免疫病理学的基本方面，涉及到暴露于和感染新型病原体。这些发现可用于改进针对新兴和既定传染病的治疗方法。
