Fig. 3: Dysfunctional monocytes in VEXAS.

a A UMAP plot of 24,887 monocytes and 704 dendritic cells (DC). b A neighborhood graph of monocytes/DCs, which was generated similarly as in Fig. 2a. c Beeswarm and box plots of monocytes/DCs for VEXAS (n = 9) and healthy donors (n = 5), which were generated similarly as in Fig. 2b. d A volcano plot of differentially expressed genes of monocytes in VEXAS as compared to healthy donor: upregulated and downregulated genes in red and blue, respectively. A horizontal dotted line represents padj = 0.05, vertical dotted lines indicate absolute log2FC values = +–0.25. P values were calculated with the two-sided Wilcoxon rank-sum test and Bonferroni correction for multiple comparisons. e A dot plot showing gene set enrichment scores of top 10 upregulated hallmark pathways across subtypes. Dot sizes indicate mean normalized enrichment score (NES) differences between VEXAS and healthy donors, and the color scale indicates FDR values; non-significant pathways (FDR ≥ 0.10) in gray. f Gene module scores of HLA class II genes and sepsis-associated monocyte signatures in monocytes across VEXAS (n = 9), healthy donors (n = 5), and other multisystem autoimmune diseases (Systemic lupus erythematosus (SLE), n = 33; microscopic polyangiitis (MPA), n = 8; Behcet’s disease (BD), n = 4). Data are presented as mean with SD. P values were calculated with the two-sided unpaired Mann–Whitney U test. g A UMAP plot of cells with projected UBA1 mutation status as wtUBA1 (981 cells) and mtUBA1 monocytes (651 cells). h Dynamic changes of mtUBA1 and wtUBA1 monocytes ratios to all monocytes in VEXAS patients (log scale on y axis) along differentiation (pseudotime ordering from classical to non-classical monocytes on x axis). Data are presented as mean with 1.96*SE. i Frequency of CSFE⁺ bait cells among CytoTell Blue⁺CD14⁺ monocytes (VEXAS, n = 6; healthy donors, n = 6). Data are presented as mean with SD. P values were calculated using the two-sided unpaired Mann–Whitney U test. j Cytokine detection of IFN-γ, IL-6, and IL-1β in culture supernatants of purified CD14⁺ monocytes (VEXAS, n = 10; healthy donors, n = 10). Data are presented as mean with SD. P values were calculated using the two-sided unpaired Mann–Whitney U test. cMono classical monocytes, intMono intermediate monocytes, ncMono non-classical monocytes, cDC conventional DCs, pDC plasmacytoid DCs. Source data are provided as a Source Data file.