Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
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DOI：
10.1084/jem.20220094
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发表时间：
2022-10-03
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本研究描述了三种新形式的常染色体隐性遗传人类TYK 2缺陷。IFN-γ的IL-23依赖性诱导的受损是患有五种已知形式的常染色体隐性TYK 2缺乏症中的任何一种的患者常见的分枝杆菌疾病的唯一机制。罕见表达缺失（LOE）TYK 2等位基因纯合子的人细胞对IFN-α/β（患者的潜在病毒性疾病）以及IL-12和IL-23（潜在分枝杆菌性疾病）的细胞应答受损，但未消除。常见P1104 A TYK 2等位基因纯合的细胞对IL-23的反应选择性受损（潜在的孤立分支杆菌疾病）。我们报告了三种新形式的TYK 2缺乏症，来自五个家族的6名患者，他们是罕见TYK 2等位基因纯合子（R864 C，G996 R，G634 E或G1010 D）或P1104 A和罕见等位基因（A928 V）的复合杂合子。所有这些错义等位基因编码可检测的蛋白质。R864 C和G1010 D等位基因在信号通路中分别是亚型和功能丧失型（LOF）。相比之下，亚型G996 R，G634 E和A928 V突变选择性地损害对IL-23的反应，如P1104 A。IFN-γ的IL-23依赖性诱导的受损是具有或不具有TYK 2表达的完全TYK 2缺陷、跨信号传导途径的部分TYK 2缺陷或对IL-23信号传导特异性的罕见或常见部分TYK 2缺陷的患者常见的分枝杆菌疾病的唯一机制。
This study characterizes three novel forms of autosomal recessive human TYK2 deficiency. Impairment of IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with any of the five known forms of autosomal recessive TYK2 deficiency. Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
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DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
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发表时间：
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期刊：
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影响因子：
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DOI：
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