137. Immunometabolism of monocytes in VEXAS syndrome is indicative of pro-inflammatory activation
Creators: name: Davide Stefanoni1, 2
name: Campochiaro3, Corrado
name: Tomelleri3, Alessandro
name: Grassini4, Greta
name: Cangi4, Maria Giulia
name: Doglioni4, Claudio
name: Dagna3, Lorenzo
name: Giulio Cavalli1, 3
Publisher: name: Zenodo
Year: 2022
Subjects: Vasculitis
ANCA
Abstracts
Giant Cell Arthritis
MPA
GPA
EGPA
Takayasu
IgA vasculitis

description: <strong>Background:</strong> VEXAS is an adult-onset inflammatory syndrome induced by an acquired mutation in the UBA1 gene<sup>1</sup>. Here, we investigated alterations in monocytes from VEXAS patients using a metabolomics-driven approach. The main purpose of this research is to highlight metabolic changes in pathways involved in the pathogenesis of this disease, paving the way for new therapeutic strategies. <strong>Methods:</strong> Two patients with VEXAS and one healthy donor were evaluated. VEXAS diagnosis was confirmed by identification of p.Met41 status by Sanger Sequencing. Ultra-High-Pressure Liquid Chromatography-Mass Spectrometry was performed on monocytes purified by negative selection from peripheral blood and evaluated in 3 technical replicates. Production of TNFα and IL-6 was assessed via ELISA assay. <strong>Results:</strong> Patient 1 was a 70-year man with fever, inflammatory arthritis, lung micronodules and skin manifestations; patient 2 was a 69-year man with polychondritis, fever, skin manifestations and lung micronodules. The healthy donor was 70-year man. Principal component analysis (PCA) showed that the metabolome of monocytes from VEXAS patients clustered independently from the control, with a PC1 higher than 50%, indicative of a profound metabolic rewiring. Hierarchical clustering analysis (HCA) of the top 50 significant metabolites confirmed these changes and clusters. T-Test analysis of the most significantly altered metabolites highlighted variations in glycolysis and TCA cycle. Specifically, pyruvate and lactate – modulators of both immune cells metabolism and cytokine production<sup>2,3</sup> - and citrate<sup>5</sup> fumarate<sup>5</sup>, and succinate<sup>4,5</sup> – fundamental for controlling immune cell phenotype and inflammation - were particularly increased in VEXAS patients. Moreover, the UBA1 mutation seeto affect Oxidative stress with a decrease in glutathione and glutathione disulfide<sup>6</sup>, polyamines, such as spermine and spermidine<sup>7</sup>, and increased sphingolipids as sphingosine-1-phosphate<sup>8</sup>. Compared to the control, VEXAS monocytes showed also a significantly enhanced production of TNFα and IL-6 (p&lt;0.01). <strong>Conclusions:</strong> We report the first data investigating the immunometabolism of VEXAS syndrome and reveal meaningful changes in pivotal metabolic pathways driven by the UBA1. These changes resemble those observed during activation (i.e. ‘trained immunity’) and likely represent the metabolic basis to enhanced cytokine production in this disease. These preliminary data highlight significant differences in essential metabolic pathways in monocytes from patients affected by VEXAS and open a new scenario for treatments targeting intermediates by-products of these metabolic processes. Further investigations in larger cohorts are mandatory. <strong>Disclosures</strong>: The authors declare no competing financial interests.