St. John's Institute of Dermatology, Guy's and St Thomas' Hospital, London, UK.
Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Scand J Immunol. 2021 Nov;94(5):e13102. doi: 10.1111/sji.13102. Epub 2021 Sep 22.
During COVID-19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil/lymphocyte ratio and monocytosis. This in turn increases IL-6 expression, which promotes scar and thrombus formation. Excess IL-6 also leads to a further reduction in NK function through downregulation of perforin expression, therefore forming a pathogenic auto-inflammatory feedback loop. The perforin/granzyme system of cytotoxicity is the main mechanism through which NK cells and cytotoxic T lymphocytes eliminate virally infected host cells, as well as being central to their role in regulating immune responses to microbial infection. Here, we present epidemiological evidence suggesting an association between perforin expression and resistance to COVID-19. In addition, we outline the manner in which a pathogenic auto-inflammatory feedback loop could operate and the relationship of this loop to genes associated with severe COVID-19. Such an auto-inflammatory loop may be amenable to synergistic multimodal therapy.
在 COVID-19 感染期间，自然杀伤 (NK) 细胞功能的降低可导致病毒清除能力受损和免疫反应失调。这种失调导致细胞因子过度产生、中性粒细胞/淋巴细胞比值升高和单核细胞增多症。这反过来又会增加白细胞介素 6 (IL-6) 的表达，促进疤痕和血栓形成。过量的 IL-6 还通过下调穿孔素的表达进一步降低 NK 功能，从而形成致病的自身炎症反馈环。细胞毒性的穿孔素/颗粒酶系统是 NK 细胞和细胞毒性 T 淋巴细胞消除病毒感染宿主细胞的主要机制，也是它们在调节对微生物感染的免疫反应中的核心作用。在这里，我们提出了流行病学证据，表明穿孔素表达与对 COVID-19 的抵抗力之间存在关联。此外，我们还概述了致病的自身炎症反馈环如何运作，以及该环与与严重 COVID-19 相关的基因之间的关系。这种自身炎症环可能适合协同的多模式治疗。
