Unexplained fever with consumptive syndrome in the elderly: two cases of VEXAS syndrome with inflammasome dysregulation

Author(s)

Mendonca, Leonardo Oliveira ; Leal, Vinicius N. C. ; Roa, Mariela E. G., V ; Barros, Samar Freschi ; Kalil, Jorge ; Pontillo, Alessandra

• Document type: Journal article
• Source: CLINICAL AND EXPERIMENTAL IMMUNOLOGY; v. 218, n. 2, p. 8-pg., 2024-09-08.

Abstract

The aim of this study is to investigate the inflammasome dysregulation in peripheral blood leukocytes of VEXAS patients. The constitutive and in vitro triggered activation of inflammasome in PBMC and neutrophils was analyzed in two Brazilian patients with typical UBA1 mutations, and compared with healthy donors. Our findings highlight the constitutive activation of caspase-1 in VEXAS leukocytes, accompanied by increased plasma levels of IL-18. Furthermore, upon stimulation of isolated peripheral blood mononuclear cells (PBMC) and neutrophils, we observed not only the exhaustion of NLRP3 and NLRP1/CARD8 pathways in VEXAS PBMC but also a significant increase in NLRP3-mediated NETs release in VEXAS neutrophils. These findings support previous studies on the contribution of the inflammasome to VEXAS pathogenesis, identifying at least two profoundly affected pathways (NLRP3 and NLRP1/CARD8) in VEXAS peripheral blood. Two VEXAS patients were analyzed for UBA1 mutations and inflammasome activation in peripheral blood leukocytes. Caspase-1 activation was observed in VEXAS leukocytes, particularly in B lymphocytes and neutrophils, which also showed NLRP3-mediated NETs release. These results emphasize the inflammasome dysregulation secondary to UBA1 mutations. Graphical Abstract (AU)

• FAPESP's process: 20/15323-3 - Disregulation of inflammasome' activation in neutrophil and endothelium in response to SARS-Cov-2 and contribution to severe COVID-19
• Grantee: Vinícius Nunes Cordeiro Leal
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 21/05420-4 - Inflammasome genetics as a risk factor for the clinical heterogeneity of SARS-Cov-2 infection
• Grantee: Alessandra Pontillo
• Support Opportunities: Regular Research Grants