Mizumaki Hiroki, Gao Shouguo, Wu Zhijie, Gutierrez-Rodrigues Fernanda, Bissa Massimiliano, Feng Xingmin, Groarke Emma M, Li Haoran, Alemu Lemlem, Raffo Diego Quinones, Darden Ivana, Kajigaya Sachiko, Grayson Peter C, Franchini Genoveffa, Young Neal S, Patel Bhavisha A
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Animal Models and Retroviral Vaccines Section, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Nat Commun. 2025 May 20;16(1):4690. doi: 10.1038/s41467-025-59890-0.
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is caused by inactivating somatic mutations in the UBA1 gene. Here, we characterize the immunological landscape of VEXAS syndrome by performing multi-omics single-cell RNA analysis, cytokine multiplex assays, and in vitro functional assays on patients' peripheral blood. Our data reveals a broad immune system activation with upregulation of multiple inflammatory response pathways and proinflammatory cytokines. Unexpectedly, we find that monocytes have dysfunctional features irrespective of UBA1 mutation status, exhibiting impaired efferocytosis and blunted cytokine production in vitro. In contrast, UBA1-mutated NK cells show an upregulation of the inflammation pathways and enhanced cytotoxicity. Within the lymphocyte subsets, predominantly UBA1 wild-type, we identify clonal expansion of effector memory CD8 T cells and skewed B cell differentiation with loss of transitional B cells and expansion of plasmablasts. Thus, our analysis indicates that VEXAS syndrome is characterized by profound alterations in both adaptive and innate immune systems, accounting for the complex pathophysiology of the disease, and provides a basis to understand the marked clinical heterogeneity and variable disease course.
VEXAS（空泡、E1酶、X连锁、自身炎症、体细胞）综合征由UBA1基因的体细胞失活突变引起。在此，我们通过对患者外周血进行多组学单细胞RNA分析、细胞因子多重检测和体外功能检测，对VEXAS综合征的免疫格局进行了表征。我们的数据揭示了广泛的免疫系统激活，多种炎症反应途径和促炎细胞因子上调。出乎意料的是，我们发现单核细胞具有功能障碍特征，与UBA1突变状态无关，在体外表现出吞噬功能受损和细胞因子产生减弱。相比之下，UBA1突变的自然杀伤细胞显示炎症途径上调和细胞毒性增强。在主要为UBA1野生型的淋巴细胞亚群中，我们鉴定出效应记忆CD8 T细胞的克隆扩增以及B细胞分化偏向，伴有过渡性B细胞丢失和成浆细胞扩增。因此，我们的分析表明，VEXAS综合征的特征是适应性和先天性免疫系统均发生深刻改变，这解释了该疾病复杂的病理生理学，并为理解显著的临床异质性和可变的病程提供了基础。
