BACKGROUND:Coronary artery lesions (CALs) are the most common and major complication of Kawasaki disease (KD) in developed countries. However, the underlying immunologic mechanisms of CAL development in KD remain unclear.METHODS:Here, we conducted single-cell transcriptome analyses of 212 210 peripheral blood mononuclear cells collected from a cross-sectional cohort of 16 children, including 4 patients with KD with CALs, 5 patients with KD without CALs, 4 healthy controls, and 3 febrile controls.RESULTS:KD altered the proportion of peripheral blood mononuclear cells, including an increasing trend in inflammatory cells (megakaryocytes and monocytes) and a decreasing trend in lymphocytes (eg, CD4⁺ T, CD8⁺ T, mucosal-associated invariant T, natural killer, and γδ T cells), highlighting the potential presence of lymphopenia phenomenon in KD. Our data indicated the presence of inflammatory cytokine storm in patients with KD with CALs, caused by systemic upregulation of TNFSF13B (tumor necrosis factor superfamily member 13b), CXCL16 (C-X-C motif chemokine ligand 16), TNFSF10 (tumor necrosis factor superfamily member 10), and IL1RN (interleukin 1 receptor antagonist), mainly produced by monocytes (especially for the Mono_CD14-CD16 cluster) and megakaryocytes. We also found that myeloid cells of patients with KD, particularly in those with CALs, might play a role in vascular injury (eg, increased MMP [matrix metalloproteinase] 9, MMP17, and MMP25) and immune cell recruitment. The immune landscape of patients with KD with CALs was featured by lower exhaustion levels in natural killer cells, a high cytotoxic state in the CD8_Pro cluster, and activation of the complement system in monocytes. Additionally, the activation of B cells was more pronounced in the early stage of KD.CONCLUSIONS:Collectively, this study provides a comprehensive understanding of the roles of various immune cells and inflammatory cytokine storms in the development of CALs in KD and offers a valuable resource for identifying novel therapeutic targets for patients with KD with CALs.

中文翻译：

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单细胞转录组揭示川崎病冠状动脉病变的潜在机制

背景：冠状动脉病变（CAL）是发达国家川崎病（KD）最常见和主要的并发症。然而，川崎病中 CAL 发展的潜在免疫学机制仍不清楚。 方法：在这里，我们对 212 210 个外周血单核细胞进行了单细胞转录组分析，这些细胞是从 16 名儿童的横断面队列中收集的，其中包括 4 名患有 CAL 的川崎病患者、5 名无 CAL 的 KD 患者、4 名健康对照者和 3 名发热对照者。结果：KD 改变了外周血单核细胞的比例，包括炎症细胞（巨核细胞和单核细胞）的增加趋势和淋巴细胞（例如， CD4 ⁺ T、CD8 ⁺ T、粘膜相关不变 T、自然杀伤细胞和 γδ T 细胞），强调了 KD 中潜在存在的淋巴细胞减少现象。我们的数据表明患有 CAL 的 KD 患者存在炎性细胞因子风暴，这是由 TNFSF13B（肿瘤坏死因子超家族成员 13b）、CXCL16（CXC 基序趋化因子配体 16）、TNFSF10（肿瘤坏死因子超家族成员 10）、 IL1RN（白细胞介素1受体拮抗剂），主要由单核细胞（特别是Mono_CD14-CD16簇）和巨核细胞产生。我们还发现，KD 患者的骨髓细胞，特别是 CAL 患者的骨髓细胞，可能在血管损伤（例如 MMP [基质金属蛋白酶] 9、MMP17 和 MMP25 增加）和免疫细胞募集中发挥作用。患有 CAL 的川崎病患者的免疫状况具有以下特点：自然杀伤细胞耗竭水平较低、CD8_Pro 簇处于高细胞毒性状态以及单核细胞中补体系统的激活。此外，B 细胞的激活在 KD 的早期阶段更为明显。 结论：总的来说，这项研究提供了对各种免疫细胞和炎症细胞因子风暴在 KD CAL 发展中的作用的全面了解，并提供了宝贵的资源为具有 CAL 的 KD 患者确定新的治疗靶点。