Inborn errors of immunity in patients with life-threatening COVID-19

项目摘要 在感染SARS-CoV-2的人中，存在巨大的个体间临床差异，从沉默到 感染致命性新冠肺炎。破解这一谜团的第一个突破来自先天错误领域 豁免(IEI)。在一项由659名患者组成的国际队列中，我们报告了23名8岁的IEIS患者。 控制依赖TLR3和IRF7的I型干扰素免疫的易感基因(3.5%)，包括4个 常染色体隐性遗传性IRF7或IFNAR1缺乏症的无关患者。我们还报告了另外101起 抗I型干扰素中和自身抗体的患者(占987人的10.2%)，他们是自身免疫的 IEI患者的表型观察。有趣的是，94%的抗I型干扰素自身抗体患者是男性， 六名患病女性中有一人患有X连锁显性色素性失禁(IP)，这表明X连锁遗传 至少在一些病人身上。总体而言，这些患者约占危及生命的COVID的13.5%- 19例为研究对象。我们现在假设导致异常(I)产生或放大的其他IEI I型干扰素，(Ii)可溶性I型干扰素的活性(通过中和自身抗体)，或(Iii)对I型干扰素的反应(根据 干扰素刺激基因活性)，可导致其他患者出现危及生命的新冠肺炎。抢断 这三个具体目标，我们受益于COVID人类基因努力的国际招募 (https://www.covidhge.com).)我们的初步数据非常强劲。首先，我们发现215名患者患有 与I型干扰素的产生或扩增相关的157个基因座上的预测功能丧失(PLOF)变体， 包括一名NLRC3中的pLOF变种纯合子患者，两名pLOF变异体杂合患者 在DDX58/RIG-I中，以及6名在I型或III型IFN亚型中pLOF变异杂合子的患者。第二，在 在抗I型干扰素自身抗体阳性的患者中，我们确定了一名X连锁SASH3中存在pLOF半合子的患者。在……里面 此外，我们发现25%的IP患者与严重的X-基因失活有关， 抗I型干扰素的自身抗体，进一步提示自身抗体与I型干扰素的产生具有X-连锁基础。第三，我们 在18个ISG中发现24名pLOF变异体患者。我们已经表明，国际开创性计划 我们只用了6个月就建立了，这是非常高效的，因为它导致了一项范式转换的发现。我们的新产品 计划将从这一势头中受益。我们未来发现的新的I型干扰素免疫先天错误 潜在的危及生命的新冠肺炎肺炎将为新的诊断和治疗策略铺平道路 以更好地管理感染SARS-CoV-2病毒的患者面临严重疾病的风险。选定的患者可能会受益 皮下或雾化干扰素-a或干扰素-b(I型干扰素产生或扩增缺陷)，血浆置换 和/或B细胞耗竭(中和抗I型IFN的自身抗体)，或其他治疗，包括抗 SARS-CoV-2(ISGs的缺陷)。

Project Summary There is immense interindividual clinical variability in humans infected with SARS-CoV-2, ranging from silent infection to lethal COVID-19. The first breakthrough to crack this enigma came from the field of inborn errors of immunity (IEI). In an international cohort of 659 patients, we reported 23 patients with IEIs at eight influenza susceptibility loci that govern TLR3- and IRF7-dependent type I interferon (IFN) immunity (3.5%), including four unrelated patients with autosomal recessive IRF7 or IFNAR1 deficiency. We also reported an additional 101 patients with neutralizing autoantibodies (auto-Abs) against type I IFN (10.2% of 987), who were auto-immune phenocopies of the patients with IEI. Interestingly, 94% of the patients with auto-Ab against type I IFN were men, and one of the six sick women had X-linked dominant incontinentia pigmenti (IP), suggesting X-linked inheritance in at least some of the patients. Collectively, these patients account for about 13.5% of life-threatening COVID- 19 cases studied. We now hypothesize that other IEI that result in abnormal (i) production or amplification of type I IFN, (ii) activity of soluble type I IFNs (via neutralizing auto-Abs), or (iii) response to type I IFN (in terms of interferon stimulated gene (ISG) activity), can underlie life-threatening COVID-19 in other patients. To tackle these three specific aims, we benefit from an international recruitment from the COVID Human Genetic Effort (https://www.covidhge.com). Our preliminary data are very strong. First, we have found 215 patients with predicted loss-of-function (pLOF) variants at 157 loci associated with production or amplification of type I IFN, including one patient homozygous for a pLOF variants in NLRC3, two patients heterozygous for pLOF variants in DDX58/RIG-I, and six patients heterozygous for pLOF variants in subtypes of type I or III IFNs. Second, among patients with auto-Ab against type I IFN, we identified a patient hemizygous for a pLOF in X-linked SASH3. In addition, we found that 25% of patients with IP, which is associated with severely skewed X-inactivation, have auto-Ab against type I IFN, further suggesting an X-linked basis of auto-Ab to type I IFN production. Third, we found 24 patients with pLOF variants in 18 ISGs. We have shown that the international path-breaking program we established in only 6 months is highly efficient, as it resulted in a paradigm-shifting discovery. Our new program will benefit from this momentum. Our future discoveries of new inborn errors of type I IFN immunity underlying life-threatening COVID-19 pneumonia will pave the way for new diagnostic and therapeutic strategies to better manage patients infected with SARS-CoV-2 at risk of severe disease. Selected patients may benefit from subcutaneous or nebulized IFN-a or IFN-b (defect in type I IFN production or amplification), plasmapheresis and/or B cell depletion (neutralizing auto-Abs against type I IFNs), or other therapies, including mAbs against SARS-CoV-2 (defects of ISGs).