Genetic mutations that impair dectin-1 function have been tied to susceptibility to fungal infection in two families, according to separate reports in the Oct. 29 issue of the New England Journal of Medicine.

In the first study, genetic assessments were performed in a large, consanguineous Iranian family to determine whether a mutated gene was responsible for their nonsyndromic fungal infections, noted Dr. Erik-Oliver Glocker of Royal Free Hospital and University College London and his associates. Many of the family members had chronic mucocutaneous candidiasis.

The index patient was a 19-year-old man who had had oral candidiasis since the age of 3 years but was otherwise healthy. This patient had a brother with intermittent thrush throughout his childhood and adolescence, and then suddenly died at age 19 of meningitis that proved to be caused by Candida species.

The mother of both boys, aged 50 at the time of the study, had had vaginal candidiasis since age 42. Her adult sister also had had oral and vaginal candidiasis since childhood, and their brother had had dermatophytosis since childhood. Both of this man’s daughters, who both died suddenly at age 15, were given postmortem diagnoses of invasive candidal meningoencephalitis.

Blood samples were obtained for DNA analysis from 36 family members and were compared with those from 50 healthy Iranian blood donors and 180 healthy white donors of other nationalities.

A previously unknown mutation in the CARD9 gene was found in 4 affected patients and 18 other relatives, but not in any of the control samples. The CARD9 gene “plays a central role in antifungal defense by receiving signals from several antifungal pattern-recognition receptors and stimulating proinflammatory responses,” the investigators noted.

“Our study shows that a homozygous point mutation in CARD9 ... is associated with a susceptibility to fungal infections,” Dr. Glocker and his colleagues wrote. The mutation impairs the function of dectin-1, a transmembrane pattern-recognition receptor that senses the beta-glucan component of fungal cell walls (N. Engl. J. Med. 2009;361:1727-35).

In the second study, genetic analyses were performed on mononuclear cells from a patient with recurrent vulvovaginal and oral or esophageal candidiasis, as well as on cells from four relatives. The patient’s two sisters had chronic onychomycosis; one of them also had recurrent vulvovaginal candidiasis. Their mother had chronic onychomycosis, and their father had transient onychomycosis.

The index patient had been found to have defective cytokine production in response to stimulation with C. albicans and with beta-glucan, indicating a potential defect in dectin-1 recognition, according to Bart Ferwerda, Ph.D., of Radboud University, Nijmegen, the Netherlands, and his associates.

The researchers identified a homozygous mutation that caused defective surface expression of dectin-1. This apparently caused an impaired cytokine response by monocytes and macrophages but did not affect the normal killing of C. albicans by neutrophils.

“The normal function of neutrophils in persons in whom dectin-1 function is absent provides protection against invasive fungal infection. In contrast, the defective function of monocytes and macrophages ... is the most likely cause of the clinical phenotype characterized by mucocutaneous fungal infections,” Dr. Ferwerda and his colleagues reported (N. Engl. J. Med. 2009;361:1760-7).

They looked for the same mutation affecting dectin-1 in samples from populations on all the major continents, seeking to assess its distribution around the world. They found it in European and African populations, which “suggests that this is an ancient mutation that most likely emerged more than 60,000 years ago, before the split of modern human populations in the late Paleolithic [period],” the investigators wrote.

Neither Dr. Glocker nor Dr. Ferwerda reported any financial conflicts of interest.

Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.

据10月29日《新英格兰医学杂志》中的两项报告显示，有损树突状细胞相关性C型植物血凝素-1(dectin-1)功能的基因突变与两个家族中真菌感染易感性之间的关系密切。

 

皇家自由医院及伦敦大学学院的Erik-Oliver Glocker博士及其同事指出，第一项研究对伊朗的一个大宗血缘家族做了基因评价，以判定突变的基因是否为其非综合征性真菌感染的原因；其中许多家族成员患有慢性皮肤黏膜念珠菌病。

 

索引患者是一个自3岁起一直患有口腔念珠菌病而其他方面均健康的19岁男性。该患者有一个兄弟在儿童期和青春期一直患有间歇性鹅口疮，在19岁时突然死于脑膜炎，经证实系念珠菌属所致。

 

这两个男孩的母亲在参加本研究时年龄为50岁，自42岁起一直患有阴道念珠菌病。她的成年妹妹也自儿童期开始一直患有口腔及阴道念珠菌病，她俩的兄弟自儿童期开始一直患有皮肤藓。这位男士的两个女儿均在15岁时猝死，尸检诊断为侵袭性念珠菌性脑膜脑炎。

 

从36个家族成员中获取血样，并与50个伊朗健康献血者的血样以及180个其他国家健康献血者的血样进行比较。

 

在4名患者和18名其他亲属的血样中发现了先前未知的胱天蛋白酶募集域蛋白9(CARD9)基因突变，但对照样本中未发现任何突变。CARD9基因“通过接收多个抗真菌免疫的模式识别受体发出的信号并激发促炎症反应，在抗真菌防御反应中起关键作用，”研究者指出。

 

“本研究显示，CARD9的纯合子点突变与真菌感染易感性有关，”Glocker博士及其同事写道。此突变可损害dectin-1——一种跨膜的可感知真菌细胞壁β-葡聚糖成分的模式识别受体——的功能(N. Engl. J. Med. 2009;361:1727-35)。

 

另一项研究对复发性外阴阴道和口腔或食管念珠菌病患者的单核细胞以及4位亲属的细胞进行基因分析。患者的2个姊妹患有慢性甲藓；其中1位同时患有复发性外阴阴道念珠菌病。他们的母亲患有慢性甲藓，父亲患暂时性甲藓。

 

据荷兰奈梅亨Radboud大学Bart Ferwerda博士及其同事指出，研究发现，索引患者在对白色念珠菌以及对β葡聚糖的刺激应答中细胞生成量不足。

 

研究者查出了一个导致表面dectin-1表达受损的纯合子突变。此突变表面上引起单核细胞和巨噬细胞介导的细胞因子应答受损，但并不影响中性粒细胞对白色念珠菌的正常杀伤力。

 

Ferwerda博士及其同事报告指出，“在dection-1功能缺失的个体中，性粒细胞功能正常，可以防御侵袭性真菌感染。相比之下，单核细胞和肥大细胞......功能缺乏极有可能是以皮肤黏膜真菌感染为特征的临床表型产生的原因。”  (N. Engl. J. Med. 2009;361:1760-7)

 

他们查找了各大洲人群样本中影响dectin-1的相同突变，旨在评价这种情况在全球的分布状况。他们在欧洲和非洲人群中发现了此突变，这“表明，此突变是一种古老的突变，极有可能出现在6万年以前，早于旧石器时代晚期现代人类种族分裂之前，”研究者写道。

 

Glocker博士及Ferwerda博士均声明无任何经济利益冲突。

 

爱思唯尔 版权所有