IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2.
IL-1 receptor antagonist, MIS-C, and the peculiar autoimmunity of SARS-CoV-2.
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DOI：
10.1016/s2665-9913(22)00090-x
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发表时间：
2022-05
期刊：
影响因子：
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通讯作者：
Canna SW
中科院分区：
文献类型：
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作者：
Bassiri H;Canna SW
www.我的天使com/rheumatology 2022年5月4日，同一研究人员报告称，约50%的严重或危重COVID-19成人存在抗IL-1 Ra自身抗体。7鉴于越来越多的证据表明过量IL-1与川崎样表型之间存在联系，8我们对这种自身抗体可能导致MIS-C的可能性很感兴趣。支持这一假设，与自身抗体阴性、川崎或安静全身性幼年特发性关节炎患者相比，抗IL-1 Ra自身抗体阳性的MIS-C患者的游离IL-1 Ra蛋白浓度较低。Western印迹显示抗体-IL-1 Ra复合物，报告基因检测表明含自身抗体的血浆可中和IL-1 Ra活性。在两名MIS-C患者的纵向随访中，自身抗体滴度下降表明这些自身抗体是一过性的。作者还提供了IL-1 Ra特异性自身免疫的潜在机制：他们在抗IL-1 Ra自身抗体阳性的MIS-C患者中鉴定了IL-1 Ra的过度磷酸化形式，但在对照组或自身抗体阴性的MIS-C患者中没有。类似地，在他们的成人COVID-19队列7和其中一名MIS-C患者中，过度磷酸化的IL-1 Ra的上升和福尔斯先于抗IL-1 Ra自身抗体的相应上升和福尔斯。这些观察结果具有挑衅性，将IL-1信号传导置于SARS-CoV-2感染的下游，但置于MIS-C患者的过度炎症的上游。然而，这项初步研究有几个局限性，包括参与者人数少，纵向样本少，和不完整的机制评估。因此，这些发现既不应影响临床决策，也不应有利于扩大阿那白滞素（重组IL-1 Ra）在MIS-C患者中的一线使用，9特别是考虑到大多数患者对IVIG和糖皮质激素的完全反应。然而，如果可以推广，这些结果激发了重要的问题（小组）。这些问题的范围和广度证明了本研究的潜在新奇和病因学重要性。在SARS-CoV-2感染后，过度磷酸化的IL-1 Ra和中和自身抗体的明显独特的关联可能会启动一个具有巨大翻译潜力的新的研究路线。在此期间，我们要感谢对SARS-CoV-2及其相关疾病做出的前所未有的科学反应，这为我们提供了对宿主病原体自身免疫问题的另一种见解。
Comment e306 www. thelancet. com/rheumatology Vol 4 May 2022 the same researchers reported anti-IL-1Ra autoantibodies in about 50% of adults with severe or critical COVID-19. 7 Given the increasing evidence of a link between excess IL-1 and Kawasaki disease-like phenotypes, 8 we are intrigued by the possibility that such autoantibodies could be contributing to MIS-C. Supporting this hypothesis, free IL-1Ra protein concentrations were lower in patients with MIS-C who were positive for anti-IL-1Ra autoantibodies, versus those who were negative for autoantibodies, or those with Kawasaki disease or quie scent systemic juvenile idiopathic arthritis. Western blots revealed antibody-IL-1Ra complexes, and reporter assays suggested neutralisation of IL-1Ra activity by autoantibody-containing plasma. Decreased autoantibody titres during longitudinal follow-up of two patients with MIS-C suggested that these autoantibodies were transient. The authors also offer a potential mechanism of IL-1Ra-specific autoimmunity: they identified a hyperphosphorylated form of IL-1Ra in the patients with MIS-C who were positive for anti-IL-1Ra autoantibodies, but not in the control groups or autoantibody-negative patients with MIS-C. Similarly, rises and falls in hyperphosphorylated IL-1Ra preceded corresponding rises and falls in anti-IL-1Ra autoantibodies in their adult COVID-19 cohort7, and in one of the patients with MIS-C.These observations are provocative, placing IL-1 signalling downstream of SARS-CoV-2 infection but upstream of hyperinflammation in patients with MIS-C. Yet, this preliminary study has several limitations, including a small number of participants, few longitudinal samples, and incomplete mechanistic evaluation. As such, these findings should neither affect clinical decision making, nor favour an expanded frontline use of anakinra (recombinant IL-1Ra) in patients with MIS-C, 9 particularly given the complete response of most patients to IVIG and glucocorticoids. However, if generalisable, these results inspire important questions (panel). The range and scope of such questions are a testament to the potential novelty and aetiological importance of this study. The apparently unique association of hyperphosphorylated IL-1Ra and neutralising autoantibodies after SARS-CoV-2 infection might launch a new line of study with great translational potential. In the interim, we can thank the unprecedented scientific response to SARS-CoV-2 and its related morbidities for another insight into the host–pathogen autoimmunity problem.