NK Cell and Monocyte Dysfunction in Multisystem Inflammatory Syndrome in Children.

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Jenna K Dick, Jules A Sangala, Venkatramana D Krishna, Aaron Khaimraj, Lydia Hamel, Spencer M Erickson, Dustin Hicks, Yvette Soigner, Laura E Covill, Alexander K Johnson, Michael J Ehrhardt, Keenan Ernste, Petter Brodin, Richard A Koup, Alka Khaitan, Carly Baehr, Beth K Thielen, Christine M Henzler, Caleb Skipper, Jeffrey S Miller, Yenan T Bryceson, Jianming Wu, Chandy C John, Angela Panoskaltsis-Mortari, Alberto Orioles, Marie E Steiner, Maxim C J Cheeran, Marco Pravetoni, Geoffrey T Hart
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引用次数: 0

Abstract

Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infection characterized by multiorgan involvement and inflammation. Testing of cellular function ex vivo to understand the aberrant immune response in MIS-C is limited. Despite strong Ab production in MIS-C, SARS-CoV-2 nucleic acid testing can remain positive for 4-6 wk postinfection. Therefore, we hypothesized that dysfunctional cell-mediated Ab responses downstream of Ab production may be responsible for delayed clearance of viral products in MIS-C. In MIS-C, monocytes were hyperfunctional for phagocytosis and cytokine production, whereas NK cells were hypofunctional for both killing and cytokine production. The decreased NK cell cytotoxicity correlated with an NK exhaustion marker signature and systemic IL-6 levels. Potentially providing a therapeutic option, cellular engagers of CD16 and SARS-CoV-2 proteins were found to rescue NK cell function in vitro. Taken together, our results reveal dysregulation in Ab-mediated cellular responses of myeloid and NK cells that likely contribute to the immune pathology of this disease.

儿童多系统炎症综合征中的 NK 细胞和单核细胞功能障碍
儿童多系统炎症综合征(MIS-C)是 SARS-CoV-2 感染的一种严重并发症,以多器官受累和炎症为特征。为了解 MIS-C 中异常免疫反应而进行的体内外细胞功能测试非常有限。尽管 MIS-C 中会产生大量抗体,但在感染后 4-6 周内,SARS-CoV-2 核酸检测仍可保持阳性。因此,我们推测,Ab产生下游的细胞介导的Ab反应失调可能是MIS-C中病毒产物清除延迟的原因。在 MIS-C 中,单核细胞的吞噬功能和细胞因子产生功能都很强,而 NK 细胞的杀伤功能和细胞因子产生功能都很弱。NK 细胞细胞毒性的降低与 NK 衰竭标记特征和全身 IL-6 水平相关。研究发现,CD16和SARS-CoV-2蛋白的细胞啮合剂可在体外挽救NK细胞的功能,这有可能提供一种治疗选择。总之,我们的研究结果揭示了 Ab 介导的骨髓细胞和 NK 细胞反应失调,这可能是导致该疾病免疫病理学的原因之一。
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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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