The Journal of allergy and clinical immunology · 2021
TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2).
СтатьяПоддержка исследования: вне правительства СШАResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод пока не подготовлен
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Deuitch Natalie T, Yang Dan, Lee Pui Y, Yu Xiaomin, Moura Natalia Sampaio, Schnappauf Oskar, Ombrello Amanda K, Stone Deborah, Kuehn Hye Sun, Rosenzweig Sergio D, Hoffmann Patrycja, Cudrici Cornelia, Levy Deborah M, Kessler Elizabeth, Soep Jennifer B, Hay Arielle D, Dalrymple Austin, Zhang Yu, Sun Li, Zhang Qiuye, Tang Xuemei, Wu Yuan, Rao Koneti, Li Haibo, Luo Hong, Zhang Yao, Burnham Jon M, Boehm Manfred, Barron Karyl, Kastner Daniel L, Aksentijevich Ivona, Zhou Qing
Аннотация
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective in treating inflammatory manifestations.
OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients.
METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment.
RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2.
CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.
OBJECTIVE: We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients.
METHODS: We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment.
RESULTS: We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients' primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2.
CONCLUSIONS: Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.