Novel compound heterozygous mutations in ZAP70 in a Chinese patient with leaky severe combined immunodeficiency disorder
Novel compound heterozygous mutations in ZAP70 in a Chinese patient with leaky severe combined immunodeficiency disorder
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DOI：
10.1007/s00251-017-0971-0
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发表时间：
2017-04-01
期刊：
影响因子：
3.2
通讯作者：
Zhang, Zhi-Yong
中科院分区：
文献类型：
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作者：
Liu, Qing;Wang, Yan-Ping;Zhang, Zhi-Yong
在人类中，酪氨酸激酶ZAP 70功能的完全缺乏导致联合免疫缺陷（CID），伴随胸腺发育异常和外周T细胞的T细胞受体（TCR）信号传导缺陷，其特征在于选择性缺乏CD8（+）T细胞。到目前为止，已经在大约20名CID患者中确定了15种独特的ZAP 70突变，具有不同的临床表现。在此，我们报告了中国首例ZAP 70新的复合杂合突变（c.598 - 599delCT，p.L200fsX28; c.847 C> T，R283H）。该患者患有早发性和复发性感染，但显示正常生长和发育，没有发育不良的迹象，因此表现为渗漏性SCID。该患者还具有自身免疫的临床表现，如湿疹性皮肤病变、炎症性肠病（IBD）和顽固性腹泻，表明T细胞致耐受性功能受损。鉴定了残余ZAP 70表达。免疫学分析显示，外周中选择性缺乏CD8（+）T细胞，而存在对植物血凝素无反应的CD4（+）T细胞。用美洲商陆有丝分裂原凝集素刺激也未能刺激患者的B细胞增殖。Tfhs和Tfxs在患者中的频率低于正常参考值。与年龄匹配的健康对照组相比，IL-17水平较高，IFN-γ、IL-4和IL-21水平较低。患有选定的CD8缺陷和严重自身免疫性疾病或过度炎症的婴儿应筛查ZAP 70缺陷。
In humans, the complete lack of tyrosine kinase ZAP70 function results in combined immunodeficiency (CID), with abnormal thymic development and defective T cell receptor (TCR) signaling of peripheral T cells, characterized by the selective absence of CD8(+) T cells. So far, 15 unique ZAP70 mutations have been identified in approximately 20 patients with CID, with variable clinical presentations. Herein, we report the first case from China of novel compound heterozygous mutations in ZAP70 (c.598-599delCT, p.L200fsX28; c.847 C > T, R283H). The patient suffered from early-onset and recurrent infections, but showed normal growth and development without signs of failure to thrive, thus presenting as leaky SCID. The patient also had clinical manifestations of autoimmunity, such as eczematous skin lesion, inflammatory bowel disease (IBD), and intractable diarrhea, suggesting compromised T cell tolerogenic functions. Residual ZAP70 expression was identified. Immunological analysis revealed the selective absence of CD8(+) T cells in the periphery and the presence of CD4(+) T cells that failed to respond to phytohemagglutinin. Stimulation with lectin from pokeweed mitogen also failed to stimulate B cell proliferation in the patient. The frequency of Tfhs and Tregs in the patient was lower compared with the normal reference. Compared with the age-matched healthy control, the level of IL-17 was higher and the levels of IFN-gamma, IL-4, and IL-21 were lower. Infants with selected CD8 deficiency and severe autoimmune disorders or exaggerated inflammation should be screened for ZAP70 deficiency.