Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation.
Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation.
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DOI：
10.1016/j.jaci.2017.08.044
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发表时间：
2018-06
期刊：
影响因子：
--
通讯作者：
Collin M
中科院分区：
文献类型：
--
作者：
Bigley V;Maisuria S;Cytlak U;Jardine L;Care MA;Green K;Gunawan M;Milne P;Dickinson R;Wiscombe S;Parry D;Doffinger R;Laurence A;Fonseca C;Stoevesandt O;Gennery A;Cant A;Tooze R;Simpson AJ;Hambleton S;Savic S;Doody G;Collin M
据报道，干扰素调节因子8(IRF8)的K108E纯合子突变可导致树突状细胞(DC)和单核细胞缺乏。然而，根据IRF8在免疫细胞发育和功能中的多重作用，可以预测更广泛的免疫功能障碍。我们试图描述IRF8复合杂合子R83C/R291Q突变对造血和免疫的影响，该突变存在于一名反复发生病毒感染、粒细胞增殖和脑内钙化的患者中。采用外显子组测序的方法对IRF8变异等位基因进行鉴定，并用报告分析法检测其功能。采用流式细胞术、功能免疫学分析、转录图谱和抗原受体图谱对细胞表型进行了详细研究。这两个突变都影响保守残基，R291Q与R294同源，R294在Bxh2 IRF8缺陷小鼠中突变。R83C显示核转位减少，两个突变体都不能调节Ets/IRF复合元件或干扰素刺激的反应元件，而R291Q保留了BATF/Jun相互作用。在血液、真皮和肺灌洗液中观察到DC缺乏和单核细胞减少。粒细胞持续增多、发育不良和功能减退。自然杀伤细胞的发育和成熟受阻。Th1、TH17和CD8+记忆性T细胞分化明显降低，T细胞不表达CXCR3。B细胞发育受损，记忆细胞减少，类别切换减少，体细胞超突变频率和复杂性降低。在干扰素和IRF8调节的转录本中，细胞特异性基因的表达受到广泛干扰。这一分析定义了人类双等位基因IRF8缺乏症的临床特征，揭示了一种由DC和单核细胞缺乏症合并广泛的免疫失调引起的复杂免疫缺陷综合征。
The homozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell (DC) and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function. We sought to describe the effect on hematopoiesis and immunity of the compound heterozygous R83C/R291Q mutation of IRF8, which is present in a patient with recurrent viral infection, granuloproliferation, and intracerebral calcification. Variant IRF8 alleles were identified by means of exome sequencing, and their function was tested by using reporter assays. The cellular phenotype was studied in detail by using flow cytometry, functional immunologic assay transcriptional profiling, and antigen receptor profiling. Both mutations affected conserved residues, and R291Q is orthologous to R294, which is mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation, and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, whereas R291Q retained BATF/JUN interactions. DC deficiency and monocytopenia were observed in blood, dermis, and lung lavage fluid. Granulocytes were consistently increased, dysplastic, and hypofunctional. Natural killer cell development and maturation were arrested. TH1, TH17, and CD8+ memory T-cell differentiation was significantly reduced, and T cells did not express CXCR3. B-cell development was impaired, with fewer memory cells, reduced class-switching, and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon- and IRF8-regulated transcripts. This analysis defines the clinical features of human biallelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by DC and monocyte deficiency combined with widespread immune dysregulation.
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影响因子：
30.5
作者：
Grajales-Reyes GE;Iwata A;Albring J;Wu X;Tussiwand R;Kc W;Kretzer NM;Briseño CG;Durai V;Bagadia P;Haldar M;Schönheit J;Rosenbauer F;Murphy TL;Murphy KM
通讯作者：
Murphy KM
DOI：
10.1084/jem.20081633
发表时间：
2009-02-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Haniffa M;Ginhoux F;Wang XN;Bigley V;Abel M;Dimmick I;Bullock S;Grisotto M;Booth T;Taub P;Hilkens C;Merad M;Collin M
通讯作者：
Collin M
影响因子：
6.4
作者：
Collin M;McGovern N;Haniffa M
通讯作者：
Haniffa M
影响因子：
2.3
作者：
Kanno, Y;Levi, BZ;Ozato, K
通讯作者：
Ozato, K
影响因子：
25
作者：
Kierdorf, Katrin;Erny, Daniel;Prinz, Marco
通讯作者：
Prinz, Marco