Vagrecha Anshul, Zhang Mingce, Acharya Suchitra, Lozinsky Shannon, Singer Aaron, Levine Chana, Al-Ghafry Maha, Fein Levy Carolyn, Cron Randy Q
Department of Pediatrics, Division of Hematology/Oncology and Cellular Therapy, Cohen Children's Medical Center, New Hyde Park, NY 11040, USA.
Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA.
Biology (Basel). 2022 Mar 9;11(3):417. doi: 10.3390/biology11030417.
Multisystem inflammatory syndrome in children (MIS-C) affects few children previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In 2020, 45 children admitted to our hospital for MIS-C underwent genetic screening with a commercial 109-immune-gene panel. Thirty-nine children were diagnosed with MIS-C, and 25.4% of the 39 MIS-C patients harbored rare heterozygous missense mutations either in primary hemophagocytic lymphohistiocytosis (pHLH) genes (LYST, STXBP2, PRF1, UNC13D, AP3B1) or the HLH-associated gene DOCK8 (four variants). We demonstrate that foamy virus introduction of cDNA for the four DOCK8 variants into human NK-92 natural killer (NK) cells led to decreased CD107a expression (degranulation) and decreased NK cell lytic function in vitro for each variant. Heterozygous carriers of missense mutations in pHLH genes and DOCK8 may serve as risk factors for development of MIS-C among children previously infected with SARS-CoV-2.
儿童多系统炎症综合征（MIS-C）影响的是少数先前感染过严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的儿童。2020年，我院收治的45例因MIS-C入院的儿童接受了一项包含109个免疫基因的商业基因检测。39名儿童被诊断为MIS-C，在这39例MIS-C患者中，25.4%在原发性噬血细胞性淋巴组织细胞增生症（pHLH）基因（LYST、STXBP2、PRF1、UNC13D、AP3B1）或HLH相关基因DOCK8（四个变异体）中携带罕见的杂合错义突变。我们证明，将这四个DOCK8变异体的cDNA导入人NK-92自然杀伤（NK）细胞的泡沫病毒导致每个变异体在体外的CD107a表达（脱颗粒）降低以及NK细胞裂解功能降低。pHLH基因和DOCK8错义突变的杂合携带者可能是先前感染SARS-CoV-2的儿童发生MIS-C的危险因素。
