Extrapulmonary Aspergillus infection in patients with CARD9 deficiency
Extrapulmonary Aspergillus infection in patients with CARD9 deficiency
复制标题
DOI：
10.1172/jci.insight.89890
复制
发表时间：
2016-10-20
期刊：
影响因子：
8
通讯作者：
Lionakis, Michail S.
中科院分区：
文献类型：
--
作者：
Rieber, Nikolaus;Gazendam, Roel P.;Lionakis, Michail S.
侵袭性肺曲霉菌病是一种危及生命的真菌病，仅影响免疫抑制、化疗引起的中性粒细胞减少、移植或先天性免疫缺陷的患者。我们研究了两名没有已知免疫缺陷的无关患者的临床、遗传学、组织学和免疫学特征，他们分别在8岁和18岁时发展为肺外侵袭性曲霉病。一名患者在12岁时死于进行性腹内曲霉病。另一名患者在9岁时出现腹内念珠菌病，18岁时发展为中枢神经系统曲菌病，25岁时发展为腹内曲菌病。两名患者均未发生肺部曲霉菌感染。1例为M1I CARD9纯合子突变，另1例为Q295X CARD9纯合子突变，均缺乏CARD9蛋白表达。患者外周血中单核细胞和Th17细胞数量正常，但他们的单核细胞在真菌特异性刺激下表现出促炎细胞因子的产生受损。中性粒细胞对烟曲霉菌的吞噬、杀伤和氧化爆发均完好无损，但尽管外周血中中性粒细胞数量正常，但两名患者均未在感染组织中积聚中性粒细胞。中性粒细胞组织聚集缺陷不是由中性粒细胞固有趋化功能缺陷引起的，提示CARD9缺乏时肺外组织中性粒细胞趋化因子的产生受到损害。综上所述，我们的结果表明，CARD9缺乏是第一个已知的遗传性或获得性疾病，易导致肺外曲霉感染并保留肺部，与感染部位中性粒细胞募集受损相关。
Invasive pulmonary aspergillosis is a life-threatening mycosis that only affects patients with immunosuppression, chemotherapy-induced neutropenia, transplantation, or congenital immunodeficiency. We studied the clinical, genetic, histological, and immunological features of 2 unrelated patients without known immunodeficiency who developed extrapulmonary invasive aspergillosis at the ages of 8 and 18. One patient died at age 12 with progressive intra-abdominal aspergillosis. The other patient had presented with intra-abdominal candidiasis at age 9, and developed central nervous system aspergillosis at age 18 and intra-abdominal aspergillosis at age 25. Neither patient developed Aspergillus infection of the lungs. One patient had homozygous M1I CARD9 (caspase recruitment domain family member 9) mutation, while the other had homozygous Q295X CARD9 mutation; both patients lacked CARD9 protein expression. The patients had normal monocyte and Th17 cell numbers in peripheral blood, but their mononuclear cells exhibited impaired production of proinflammatory cytokines upon fungus-specific stimulation. Neutrophil phagocytosis, killing, and oxidative burst against Aspergillus fumigatus were intact, but neither patient accumulated neutrophils in infected tissue despite normal neutrophil numbers in peripheral blood. The neutrophil tissue accumulation defect was not caused by defective neutrophil-intrinsic chemotaxis, indicating that production of neutrophil chemoattractants in extrapulmonary tissue is impaired in CARD9 deficiency. Taken together, our results show that CARD9 deficiency is the first known inherited or acquired condition that predisposes to extrapulmonary Aspergillus infection with sparing of the lungs, associated with impaired neutrophil recruitment to the site of infection.