川崎病和儿童多系统炎症综合征中瞬态抗细胞因子自身抗体加重炎症反应：疾病相关性的对比队列研究

Transient anti-cytokine autoantibodies superimpose the hyperinflammatory response in Kawasaki disease and multisystem inflammatory syndrome in children: a comparative cohort study on correlates of disease.

机构信息

Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center (Amsterdam UMC), University of Amsterdam (UvA), Amsterdam, the Netherlands.

出版信息

EBioMedicine. 2023 Sep;95:104736. doi: 10.1016/j.ebiom.2023.104736. Epub 2023 Jul 29.

DOI:10.1016/j.ebiom.2023.104736

PMID:37524002

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10403726/

Abstract

BACKGROUND

Children with SARS-CoV-2 related Multisystem Inflammatory Syndrome in Children (MIS-C) often present with clinical features that resemble Kawasaki disease (KD). Disease severity in adult COVID-19 is associated to the presence of anti-cytokine autoantibodies (ACAAs) against type I interferons. Similarly, ACAAs may be implicated in KD and MIS-C. Therefore, we explored the immunological response, presence of ACAAs and disease correlates in both disorders.

METHODS

Eighteen inflammatory plasma protein levels and seven ACAAs were measured in KD (n = 216) and MIS-C (n = 56) longitudinally by Luminex and/or ELISA. Levels (up to 1 year post-onset) of these proteins were related to clinical data and compared with healthy paediatric controls.

FINDINGS

ACAAs were found in both patient groups. The presence of ACAAs lagged behind the inflammatory plasma proteins and peaked in the subacute phase. ACAAs were mostly directed against IFN-γ (>80%) and were partially neutralising at best. KD presented with a higher variety of ACAAs than MIS-C. Increased levels of anti-IL-17A (P = 0·02) and anti-IL-22 (P = 0·01) were inversely associated with ICU admission in MIS-C. Except for CXCL10 in MIS-C (P = 0·002), inflammatory plasma proteins were elevated in both KD and MIS-C. Endothelial angiopoietin-2 levels were associated with coronary artery aneurysms in KD (P = 0·02); and sCD25 (P = 0·009), angiopoietin-2 (P = 0·001), soluble IL-33-receptor (ST2, P = 0·01) and CXCL10 (P = 0·02) with ICU admission in MIS-C.

INTERPRETATION

Markers of endothelial activation (E-selectin, angiopoietin-2), and innate and adaptive immune responses (macrophages [CD163, G-CSF], neutrophils [lipocalin-2], and T cells [IFN-γ, CXCL10, IL-6, IL-17]), are upregulated in KD and MIS-C. ACAAs were detected in both diseases and, although only partly neutralising, their transient presence and increased levels in non-ICU patients may suggest a dampening role on inflammation.

FUNDING

The Kawasaki study is funded by the Dutch foundation Fonds Kind & Handicap and an anonymous donor. The sponsors had no role in the study design, analysis, or decision for publication.

摘要

背景

患有与 SARS-CoV-2 相关的儿童多系统炎症综合征 (MIS-C) 的儿童常出现类似于川崎病 (KD) 的临床特征。成人 COVID-19 的疾病严重程度与存在针对 I 型干扰素的抗细胞因子自身抗体 (ACAAs) 有关。同样，ACAAs 可能与 KD 和 MIS-C 有关。因此，我们探索了这两种疾病的免疫反应、ACAAs 的存在和疾病相关性。

方法

通过 Luminex 和/或 ELISA 纵向测量 KD（n=216）和 MIS-C（n=56）中 18 种炎症血浆蛋白水平和 7 种 ACAAs。这些蛋白的水平（发病后长达 1 年）与临床数据相关，并与健康儿科对照进行比较。

结果

在两个患者组中均发现了 ACAAs。ACAAs 的出现滞后于炎症血浆蛋白，并在亚急性期达到高峰。ACAAs 主要针对 IFN-γ（>80%），最多只能部分中和。KD 比 MIS-C 表现出更多种类的 ACAAs。MIS-C 中抗 IL-17A（P=0.02）和抗 IL-22（P=0.01）水平升高与 ICU 入院呈负相关。除了 MIS-C 中的 CXCL10（P=0.002）外，KD 和 MIS-C 中均升高了炎症血浆蛋白。血管内皮细胞的血管生成素-2 水平与 KD 的冠状动脉瘤有关（P=0.02）；可溶性 CD25（P=0.009）、血管生成素-2（P=0.001）、可溶性 IL-33 受体（ST2，P=0.01）和 CXCL10（P=0.02）与 MIS-C 的 ICU 入院相关。

解释

血管内皮细胞激活标志物（E-选择素、血管生成素-2）以及先天和适应性免疫反应标志物（巨噬细胞[CD163、G-CSF]、中性粒细胞[脂钙素-2]和 T 细胞[IFN-γ、CXCL10、IL-6、IL-17]）在 KD 和 MIS-C 中均上调。在这两种疾病中均检测到 ACAAs，尽管仅部分中和，但它们的短暂存在和非 ICU 患者中水平升高可能表明它们对炎症具有抑制作用。