VEXAS syndrome is characterized by inflammasome activation and monocyte dysregulation

• Published in: Nature communications Vol. 15; no. 1; pp. 910 - 17
• Main Authors: Kosmider, Olivier, Possémé, Céline, Templé, Marie, Corneau, Aurélien, Carbone, Francesco, Duroyon, Eugénie, Breillat, Paul, Chirayath, Twinu-Wilson, Oules, Bénédicte, Sohier, Pierre, Luka, Marine, Gobeaux, Camille, Lazaro, Estibaliz, Outh, Roderau, Le Guenno, Guillaume, Lifermann, François, Berleur, Marie, Le Mene, Melchior, Friedrich, Chloé, Lenormand, Cédric, Weitten, Thierry, Guillotin, Vivien, Burroni, Barbara, Boussier, Jeremy, Willems, Lise, Aractingi, Selim, Dionet, Léa, Tharaux, Pierre-Louis, Vergier, Béatrice, Raynaud, Pierre, Ea, Hang-Korng, Ménager, Mickael, Duffy, Darragh, Terrier, Benjamin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.01.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/21; 13/31; 14/32; 14/63; 45; 45/77; 45/91; 631/250/232/2059; 631/250/249; 631/250/256; 692/420/256/2177; Adult; Blood circulation; Cell activation; Cell death; Chemokine receptors; Enzymes; Gene expression; Humanities and Social Sciences; Humans; Immunology; Inflammasomes; Inflammation; Isoforms; Life Sciences; Monocytes; multidisciplinary; Mutation; Myelodysplastic Syndromes; Myeloid Cells; NF-κB protein; Peripheral blood; Prospective Studies; Science; Science (multidisciplinary); Skin Diseases, Genetic; Therapeutic targets; Tumor necrosis factor-α; Vacuoles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-44811-4

Acquired mutations in the UBA1 gene were recently identified in patients with severe adult-onset auto-inflammatory syndrome called VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic). However, the precise physiological and clinical impact of these mutations remains poorly defined. Here we study a unique prospective cohort of VEXAS patients. We show that monocytes from VEXAS are quantitatively and qualitatively impaired and display features of exhaustion with aberrant expression of chemokine receptors. In peripheral blood from VEXAS patients, we identify an increase in circulating levels of many proinflammatory cytokines, including IL-1β and IL-18 which reflect inflammasome activation and markers of myeloid cells dysregulation. Gene expression analysis of whole blood confirms these findings and also reveals a significant enrichment of TNF-α and NFκB signaling pathways that can mediate cell death and inflammation. This study suggests that the control of the nflammasome activation and inflammatory cell death could be therapeutic targets in VEXAS syndrome. Acquired mutations of the gene UBA1 occurring in myeloid cells that result in the expression of impaired isoforms of the enzyme E1 have been described in patients with a severe adult onset auto-inflammatory syndrome called VEXAS. Here the authors profile patients with UBA1 mutations presenting with or without VEXAS disease and show VEXAS disease is characterized by inflammasome activation and monocyte dysregulation.