Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Columbia University Medical Center, New York, NY.
Department of Medicine, Division of Rheumatology, Center for Clinical and Translational Immunology, Columbia University Medical Center, New York, NY.
J Allergy Clin Immunol. 2022 Mar;149(3):912-922. doi: 10.1016/j.jaci.2021.10.015. Epub 2021 Oct 22.
Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete.
Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC).
MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP).
Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11cCD141CLEC9A) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56/CD57/KLRG/CD161/CD38 natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome.
Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.
儿童多系统炎症综合征（MIS-C）是一种急性、发热、与严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）相关的综合征，常伴有心血流动力学功能障碍。对疾病机制的了解仍不完整。
我们的目的是分析与发热对照组（FC）相比，MIS-C 患者的免疫特征。
MIS-C 患者的定义标准较窄，包括有证据表明存在心血流动力学受累且无巨噬细胞活化综合征。从 8 名完全未经治疗的 MIS-C 患者（SARS-CoV-2 血清学阳性）、3 名未分类的 MIS-C 样疾病患者（血清学阴性）、14 名 FC 和 5 名 MIS-C 恢复（RCV）患者中采集样本。使用流式细胞术检测抗原呈递细胞（APCs）中的 36 个参数和 T 细胞中的 29 个参数。我们使用双轴分析和一致流形逼近和投影（UMAP）。
与 FC 相比，MIS-C 中发现细胞因子如 CXCL9、M-CSF 和 IL-27 显著升高。与健康对照组相比，经典单核细胞和 2 型树突状细胞（DCs）下调（CD86、HLA-DR 降低）；然而，与 FC 相比，1 型 DC（CD11cCD141CLEC9A）在 MIS-C 患者中高度激活，表达更高水平的 CD86、CD275 和非典型常规 DC 标志物，如 CD64、CD115 和 CX3CR1。多个单核细胞亚型中 CD169 和 CD38 上调。CD56/CD57/KLRG/CD161/CD38 自然杀伤（NK）细胞是 MIS-C 与无巨噬细胞活化综合征的 FC 之间的独特亚群。
复杂细胞因子信号的协调作用、1 型 DC 激活和 NK 失调是 MIS-C 病理生理学的关键特征。NK 细胞的发现可能提示与巨噬细胞活化综合征有关，而 1 型 DC 的上调暗示了抗原交叉呈递的作用。
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