In depth transcriptomic profiling defines a landscape of dysfunctional immune responses in patients with VEXAS syndrome

Hiroki Mizumaki, Shouguo Gao, Zhijie Wu (), Fernanda Gutierrez-Rodrigues, Massimiliano Bissa, Xingmin Feng, Emma M. Groarke, Haoran Li, Lemlem Alemu, Diego Quinones Raffo, Ivana Darden, Sachiko Kajigaya, Peter C. Grayson, Genoveffa Franchini, Neal S. Young () and Bhavisha A. Patel
Additional contact information
Hiroki Mizumaki: National Institutes of Health
Shouguo Gao: National Institutes of Health
Zhijie Wu: National Institutes of Health
Fernanda Gutierrez-Rodrigues: National Institutes of Health
Massimiliano Bissa: National Institutes of Health
Xingmin Feng: National Institutes of Health
Emma M. Groarke: National Institutes of Health
Haoran Li: National Institutes of Health
Lemlem Alemu: National Institutes of Health
Diego Quinones Raffo: National Institutes of Health
Ivana Darden: National Institutes of Health
Sachiko Kajigaya: National Institutes of Health
Peter C. Grayson: National Institutes of Health
Genoveffa Franchini: National Institutes of Health
Neal S. Young: National Institutes of Health
Bhavisha A. Patel: National Institutes of Health

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59890-0

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