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

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: CLINICAL AND EXPERIMENTAL IMMUNOLOGY; v. 218, n. 2, p. 8-pg., 2024-09-08.

Resumo

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)

• Processo FAPESP: 20/15323-3 - Desregulação do inflamassoma na ativação de neutrófilos e endotélio em resposta a SARS-CoV-2 e contribuição para desenvolvimento de COVID-19 grave
• Beneficiário: Vinícius Nunes Cordeiro Leal
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 21/05420-4 - Genética do inflamassoma como possível fator de risco para a heterogeneidade clinica da infeção por SARS-CoV-2
• Beneficiário: Alessandra Pontillo
• Modalidade de apoio: Auxílio à Pesquisa - Regular