Impaired Specific Antifungal Immunity in CARD9-Deficient Patients with Phaeohyphomycosis
Impaired Specific Antifungal Immunity in CARD9-Deficient Patients with Phaeohyphomycosis
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CARD9 缺陷的褐丝菌病患者特异性抗真菌免疫力受损
DOI：
10.1016/j.jid.2017.10.009
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发表时间：
2018-03-01
影响因子：
6.5
通讯作者：
Li, Ruoyu
中科院分区：
文献类型：
--
作者：
Wang, Xiaowen;Zhang, Ruijun;Li, Ruoyu
暗色丝孢霉病是一组由暗色真菌引起的严重感染。我们以前确定了CARD 9的缺陷，在4名中国患者与phaeohyphomycosis引起的瓶霉疣。在这项研究中，我们试图确定罕见的暗色真菌感染的遗传和免疫学机制，在其他健康的患者与由外瓶霉spinifera，Ochroconis musae，Corynespora dumicola引起的暗色丝孢真菌病。这些患者的CARD 9测序显示，据我们所知，一个突变（p.S23X）尚未表征，两个先前表征的突变（p.D274fsX60和p.L64fsX59）导致CARD 9蛋白表达缺失。患者来源的CARD 9缺陷细胞在真菌特异性刺激后显示出促炎细胞因子和趋化因子产生、NF-κ B活化以及22型辅助T细胞和17型辅助T细胞相关反应的选择性损害，而吞噬作用和活性氧簇产生则完好无损。一致的是，Card 9基因敲除小鼠对暗色丝孢霉病高度易感，并表现出与患者相似的免疫缺陷，包括在局部和体外功能研究中NF-κ B和p38 MAPK活化减少。这项工作澄清了遗传性CARD 9缺陷和暗色丝孢菌病之间的关联，并进一步加深了目前对CARD 9缺陷引起的疾病谱和病理生理学的了解。
Phaeohyphomycosis is a group of severe infections caused by dematiaceous fungi. We previously identified CARD9 deficiencies in four Chinese patients with phaeohyphomycosis caused by Phialophora verrucosa. In this study, we sought to identify the genetic and immunological mechanisms underlying rare dematiaceous fungal infections in three otherwise healthy patients with phaeohyphomycosis caused by Exophiala spinifera, Ochroconis musae, and Corynespora cassiicola. CARD9 sequencing in these patients showed one mutation (p.S23X) that, to our knowledge, has not been characterized and two previously characterized mutations (p.D274fsX60 and p.L64fsX59) that led to lack of CARD9 protein expression. Patient-derived CARD9-deficient cells showed a selective impairment of proinflammatory cytokine and chemokine production, NF-kappa B activation, and T helper type 22- and T helper type 17-associated responses upon fungus-specific stimulation, whereas phagocytosis and reactive oxygen species production were intact. Consistently, Card9-knockout mice were highly susceptible to phaeohyphomycosis and exhibited immune deficiencies similar to those of patients, including diminished NF-kappa B and p38 MAPK activation in local and in vitro functional studies. This work clarifies the association between inherited CARD9 deficiencies and phaeohyphomycosis, and furthers current knowledge on the spectrum and pathophysiology of diseases resulting from CARD9 deficiencies.