Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes.
Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes.
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DOI：
10.1016/j.coi.2012.04.011
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发表时间：
2012-08
影响因子：
7
通讯作者：
Casanova JL
中科院分区：
文献类型：
--
作者：
Boisson-Dupuis S;Kong XF;Okada S;Cypowyj S;Puel A;Abel L;Casanova JL
▶常染色体隐性功能完全丧失的STAT1缺乏症易患分枝杆菌和病毒性疾病。▶常染色体隐性部分功能丧失STAT1缺乏症易患轻度分枝杆菌病和病毒性疾病。▶常染色体显性功能缺失STAT1缺乏症易患分枝杆菌病。▶常染色体显性功能获得性STAT1障碍易患慢性黏膜皮肤病。人类各种传染病的遗传解剖导致了人类STAT1免疫的四种类型的先天错误的定义，包括(I)常染色体隐性(AR)完全STAT1缺陷，(Ii)AR部分STAT1缺陷，(Iii)常染色体显性(AD)STAT1缺陷，和(Iv)AD STAT1活性增强。这两种类型的AR STAT1缺陷导致广泛的感染表型，对巨噬细胞内细菌(主要是分枝杆菌)和病毒(至少是疱疹病毒)的易感性，主要是由于干扰素-γ和干扰素-α/β介导的免疫功能受损。临床结果取决于STAT1缺陷降低对这些细胞因子的反应性的程度。由于干扰素-γ介导的免疫功能受损，当干扰素-α/β介导的免疫功能得以维持时，AD STAT1缺乏症选择性地使个体易患分枝杆菌病。最后，AD中STAT1活性的增加与自身免疫有关，可能是由于干扰素-α/β介导的免疫增强。更令人惊讶的是，它还与慢性皮肤粘膜念珠菌病有关，其机制尚未确定，涉及抑制产生IL-17的T细胞的发展。因此，人类STAT1的生殖系突变定义了四种不同的临床疾病。因此，病毒、分枝杆菌和真菌感染的各种组合在人类STAT1基因座上是等位的。《自然》杂志的这些实验巧妙地突出了人类对感染表型的遗传解剖对临床和免疫学的影响。
▶ Autosomal recessive complete loss-of-function STAT1 deficiency predisposes to mycobacterial and viral diseases. ▶ Autosomal recessive partial loss-of-function STAT1 deficiency predisposes to mild mycobacterial and viral diseases. ▶ Autosomal dominant loss-of-function STAT1 deficiency predisposes to mycobacterial disease. ▶ Autosomal dominant gain-of-function STAT1 disorder predisposes to chronic mucocutaneous disease. The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-γ-mediated and IFN-α/β-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-γ-mediated immunity, as IFN-α/β-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-α/β-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral, mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.
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影响因子：
3.6
作者：
Averbuch, Diana;Chapgier, Ariane;Engelhard, Dan
通讯作者：
Engelhard, Dan
影响因子：
4.4
作者：
Chapgier, Ariane;Wynn, Robert F.;Arkwright, Peter D.
通讯作者：
Arkwright, Peter D.
影响因子：
6.4
作者：
de Wit, Emmie;Munster, Vincent J.;Feldmann, Heinz
通讯作者：
Feldmann, Heinz
DOI：
10.1073/pnas.86.4.1203
发表时间：
1989-02-01
影响因子：
11.1
作者：
DALE, TC;IMAM, AMA;STARK, GR
通讯作者：
STARK, GR
影响因子：
3.7
作者：
Boisson-Dupuis, Stephanie;El Baghdadi, Jamila;Casanova, Jean-Laurent
通讯作者：
Casanova, Jean-Laurent