文献检索，用中文搜 PubMed

BACKGROUND

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.

OBJECTIVE

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.

METHODS

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.

RESULTS

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. T1, T17, 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.

CONCLUSIONS

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.

背景

干扰素调节因子 8（IRF8）的纯合 K108E 突变已被报道可导致树突状细胞（DC）和单核细胞缺乏。然而，IRF8 在免疫细胞发育和功能中的多种作用表明可能会导致更广泛的免疫功能障碍。

目的

我们试图描述 IRF8 的复合杂合 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、粒细胞增生和颅内钙化的患者中。

方法

通过外显子组测序鉴定变异的 IRF8 等位基因，并通过报告基因测定测试其功能。通过流式细胞术、功能免疫测定、转录谱分析和抗原受体谱分析详细研究细胞表型。

结果

这两种突变都影响了保守残基，R291Q 与 BXH2IRF8 缺陷型小鼠中突变的 R294 是同源的。R83C 显示核易位减少，两种突变体均不能调节 Ets/IRF 复合元件或干扰素刺激反应元件，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。粒细胞持续增加、发育不良和功能低下。自然杀伤细胞发育和成熟受阻。T1、T17 和 CD8 记忆 T 细胞分化明显减少，T 细胞不表达 CXCR3。B 细胞发育受损，记忆细胞减少，类别转换减少，体细胞高频突变的频率和复杂性降低。干扰素和 IRF8 调节转录物中的细胞特异性基因表达广泛受到干扰。