Divisão de Imunologia Clínica e Alergia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (USP), São Paulo, Brazil.
Divisão de Imunologia Clínica e Alergia, Centro de Doenças Raras e da Imunidade, Rede DASA - Hospital Nove de Julho, São Paulo, Brazil.
Clin Exp Immunol. 2024 Oct 16;218(2):213-220. doi: 10.1093/cei/uxae069.
The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analyzed in two Brazilian patients with typical UBA1 mutations, and compared with healthy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood.
本研究旨在探讨 VEXAS 患者外周血白细胞中炎症小体的失调。分析了两名具有典型 UBA1 突变的巴西患者和健康供体的 PBMC 和中性粒细胞中炎症小体的组成性和体外触发激活情况。我们的研究结果强调了 VEXAS 白细胞中 caspase-1 的组成性激活，同时伴有 IL-18 血浆水平升高。此外，在刺激分离的外周血单核细胞（PBMC）和中性粒细胞时，我们不仅观察到 VEXAS PBMC 中 NLRP3 和 NLRP1/CARD8 途径的衰竭，而且观察到 VEXAS 中性粒细胞中 NLRP3 介导的 NETs 释放显著增加。这些发现支持了先前关于炎症小体对 VEXAS 发病机制的贡献的研究，确定了至少两种在 VEXAS 外周血中受到严重影响的途径（NLRP3 和 NLRP1/CARD8）。
