Combined immunodeficiency associated with DOCK8 mutations.
Combined immunodeficiency associated with DOCK8 mutations.
复制标题
DOI：
10.1056/nejmoa0905506
复制
发表时间：
2009-11-19
期刊：
影响因子：
--
通讯作者：
Su HC
中科院分区：
文献类型：
--
作者：
Zhang Q;Davis JC;Lamborn IT;Freeman AF;Jing H;Favreau AJ;Matthews HF;Davis J;Turner ML;Uzel G;Holland SM;Su HC
复发性肺和皮肤病毒感染伴血清IgE水平升高是某些联合免疫缺陷变异体的特征。这些变异的遗传原因尚不清楚。我们收集了来自8个家庭的11例复发性肺和皮肤病毒感染患者的纵向临床资料。我们进行了比较基因组杂交阵列和靶向基因测序。预测表达缺失突变的变异通过定量逆转录酶-聚合酶链反应测定和免疫印迹法确认。我们利用体外实验和流式细胞术评估淋巴细胞的数量和功能。患者有复发性中耳炎、鼻窦炎和肺炎；复发性金黄色葡萄球菌皮肤感染伴外耳炎；复发性、严重的单纯疱疹病毒或带状疱疹感染；传染性软疣广泛和持续感染；以及人类乳头瘤病毒感染。大多数患者有严重的变态反应伴过敏反应；几个人患有鳞状细胞癌，一个人患有t细胞淋巴瘤-白血病。血清IgE水平升高、嗜酸性粒细胞增多、T细胞和B细胞数量低、血清IgM水平低和可变的IgG抗体反应是常见的。活化的CD8 T细胞在体外扩增受损。编码胞质分裂献身蛋白（DOCK8）的基因出现新的纯合或复合杂合缺失和点突变，导致淋巴细胞中DOCK8蛋白缺失。常染色体隐性DOCK8缺陷与一种新型的联合免疫缺陷相关。
Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss-of-expression mutations were confirmed by means of a quantitative reverse-transcriptase –polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous-cell carcinomas, and one had T-cell lymphoma –leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency.