Division of Pediatric Infectious Diseases and Immunology, Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center (IIDRC), Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pediatrics, Cedars-Sinai Medical Center, and David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Division of Pediatric Infectious Diseases and Immunology, Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center (IIDRC), Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Immunity. 2019 Sep 17;51(3):508-521.e6. doi: 10.1016/j.immuni.2019.05.021. Epub 2019 Aug 27.
Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
最近的实验数据以及来自患者的临床、遗传和转录组证据表明，白细胞介素-1β（IL-1β）在川崎病（KD）的发病机制中起关键作用。然而，KD 血管炎期间心血管损伤发展的分子机制尚不清楚。在这里，我们研究了 KD 血管炎中的肠道屏障功能，观察到 KD 患者存在肠道通透性证据和循环分泌型免疫球蛋白 A（sIgA）升高，以及 KD 血管炎小鼠模型中血管组织中升高的 sIgA 和 IgA 沉积。靶向肠道通透性可纠正肠道通透性，防止 IgA 沉积并改善小鼠模型的心血管病理。通过 IL-1β 信号的遗传和药物抑制，我们证明 IL-1β位于肠道屏障功能障碍、随后的 IgA 血管炎发展和心脏炎症的上游。针对黏膜屏障功能障碍和 IL-1β 途径也可能适用于其他 IgA 相关疾病，包括 IgA 血管炎和 IgA 肾病。
