TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2)
TNF inhibition in vasculitis management in adenosine deaminase 2 deficiency (DADA2)
复制标题
腺苷脱氨酶 2 缺乏症 (DADA2) 的血管炎管理中的 TNF 抑制
DOI：
10.1016/j.jaci.2021.10.030
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发表时间：
2022-05-04
影响因子：
14.2
通讯作者：
Zhou, Qing
中科院分区：
文献类型：
--
作者：
Deuitch, Natalie T.;Yang, Dan;Zhou, Qing
背景资料：腺苷脱氨酶2（DADA 2）缺乏症是一种由功能性ADA 2蛋白缺失引起的复发性遗传性自身炎症性疾病。肿瘤坏死因子抑制（TNFi）已被证明是非常有效的治疗炎症increasing.Objective：我们试图探讨这些patients.Methods的病理生理和TNF抑制剂反应的潜在机制：我们进行桑格测序的ADA 2基因。我们使用流式细胞术，细胞内细胞因子染色，转录组分析，免疫组织化学和细胞分化实验，以确定在DADA 2患者的炎症签名，并研究了他们对TNF-抑制剂treatment.Results的反应：我们证明了增加的炎症信号和过度生产的IFN和核因子κ B途径介导的细胞因子在患者的原代细胞。用TNFi治疗导致炎症减少，挽救了向促炎性M1巨噬细胞亚群的偏斜分化，并恢复了血管中内皮细胞的完整性。我们还报告了7例DADA 2患者的8种新的疾病相关变异。结论：我们的数据探索了TNFi治疗DADA 2有效治疗的细胞机制。DADA 2血管炎与活化的髓样细胞的存在密切相关，并且内皮细胞损伤通过抗TNF治疗得以挽救。
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.