Laboratory of Immunobiology and Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Belgium.
Laboratory of Immunobiology and Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, KU Leuven, Belgium.
Cytokine Growth Factor Rev. 2021 Apr;58:134-140. doi: 10.1016/j.cytogfr.2021.01.004. Epub 2021 Jan 29.
Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by autoantibodies come with more severe COVID-19. However, there is more, as the SARS-CoV-2 dysregulates not only innate immune mechanisms but also T and B cell repertoires. Most genetic, hematological and immunological studies in COVID-19 are at present phenomenological. However, these and antecedent studies contain the seed grains to resolve many unanswered questions and a whole range of testable hypotheses. What are the links, if existing, between genetics and the occurrence of interferon-neutralizing antibodies? Are NAGGED (neutralizing and generated by gene defect) antibodies involved or not? Is the autoimmune process cause or consequence of virus infection? What are the roles played by cytokine posttranslational modifications, such as proteolysis, glycosylation, citrullination and others? How is systemic autoimmunity linked with type 1 interferons? These questions place cytokines and growth factors at pole positions as keys to unlock basic mechanisms of infection and (auto)immunity. Related to cytokine research, (1) COVID-19 patients develop neutralizing autoantibodies, mainly against alpha interferons and it is not yet established whether this is the consequence or cause of virus replication. (2) The glycosylation of recombinant interferon-beta protects against breaking tolerance and the development of neutralizing antibodies. (3) SARS-CoV-2 induces severe inflammation and release of extracellular proteases leading to remnant epitopes, e.g. of cytokines. (4) In the rare event of homozygous cytokine gene segment deletions, observed neutralizing antibodies may be named NAGGED antibodies. (5) Severe cytolysis releases intracellular content into the extracellular milieu and leads to regulated degradation of intracellular proteins and selection of antibody repertoires, similar to those observed in patients with systemic lupus erythematosus. (6) Systematic studies of novel autoimmune diseases on single cytokines will complement the present picture about interferons. (7) Interferon neutralization in COVID-19 constitutes a preamble of more studies about cytokine-regulated proteolysis in the control of autoimmunity. Here we reformulate these seven conjectures into testable questions for future research.
干扰素是目前体外对抗 SARS-CoV-2 的最佳抗病毒药物，而其信号级联中的遗传缺陷或自身抗体对阿尔法干扰素的中和作用与更严重的 COVID-19 有关。然而，不仅如此，SARS-CoV-2 不仅失调了先天免疫机制，还失调了 T 和 B 细胞库。目前，COVID-19 的大多数遗传、血液学和免疫学研究都是现象学的。然而，这些和先前的研究包含了解决许多未回答问题和一系列可测试假设的种子。如果存在的话，遗传与干扰素中和抗体的发生之间有什么联系？是否涉及 NAGGED（中和并由基因缺陷产生）抗体？自身免疫过程是病毒感染的原因还是后果？细胞因子翻译后修饰（如蛋白水解、糖基化、瓜氨酸化等）的作用是什么？全身性自身免疫与 I 型干扰素有什么关系？这些问题将细胞因子和生长因子置于关键位置，作为解开感染和（自身）免疫基本机制的关键。与细胞因子研究相关的有：（1）COVID-19 患者会产生中和自身抗体，主要针对阿尔法干扰素，目前尚不清楚这是病毒复制的结果还是原因。（2）重组干扰素-β的糖基化可防止打破耐受和产生中和抗体。（3）SARS-CoV-2 诱导严重炎症和细胞外蛋白酶的释放，导致残余表位，例如细胞因子。（4）在罕见的细胞因子基因片段纯合缺失情况下，观察到的中和抗体可能被命名为 NAGGED 抗体。（5）严重的细胞溶解会将细胞内物质释放到细胞外环境中，并导致细胞内蛋白质的调节降解和抗体库的选择，类似于系统性红斑狼疮患者的情况。（6）对单一细胞因子的新型自身免疫性疾病的系统研究将补充目前关于干扰素的研究。（7）COVID-19 中的干扰素中和构成了更多关于细胞因子调节的蛋白水解在自身免疫控制中的研究的序幕。在这里，我们将这七个假设重新表述为未来研究的可测试问题。
