In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ
In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ
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DOI：
10.1172/jci9166
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发表时间：
2000-05-01
影响因子：
15.9
通讯作者：
Casanova, JL
中科院分区：
文献类型：
--
作者：
Jouanguy, E;Dupuis, S;Casanova, JL
完全性IFN γ受体配体结合链（IFN γ R1）缺乏症是一种危及生命的常染色体隐性免疫疾病。迄今为止鉴定的致病性IFNGR 1突变包括无义和剪接突变以及移码缺失和插入。所有的结果在一个过早的终止密码子上游编码的跨膜结构域的片段，排除细胞表面表达的受体，我们在此报告两个散发和两个家族性的情况下，一种新的形式的完全IFN γ R1缺乏症，其中正常数量的受体在细胞表面检测。在编码受体细胞外配体结合结构域的片段中发现了两个框内缺失和两个错义IFNGR 1突变。八个独立的IFN γ R1特异性mAb，包括七个阻断抗体，给出了患者之间不同的识别模式，表明不同的表位被突变改变。然而，在任何患者中均未观察到I-125-IFN-γ与细胞的特异性结合，并且细胞未能对IFN-γ产生应答。因此，这些突变通过破坏IFN-γ结合位点而不影响表面表达，从而导致完全的IFN-γ R1缺乏症。通过特异性抗体（包括封闭抗体）检测表面IFN-γ R1分子，并不排除完全的IFN-γ R1缺乏症的诊断。
Complete IFN-gamma receptor ligand-binding chain (IFN gamma R1) deficiency is a life-threatening autosomal recessive immune disorder, Affected children invariably die of mycobacterial infection, unless bone marrow transplantation is undertaken. Pathogenic IFNGR1 mutations identified to date include nonsense and splice mutations and frameshift deletions and insertions. All result in a premature stop codon upstream from the segment encoding the transmembrane domain, precluding cell surface expression of the receptors, We report herein two sporadic and two familial cases of a novel form of complete IFN gamma R1 deficiency in which normal numbers of receptors are detected at the cell surface. Two in-frame deletions and two missense IFNGR1 mutations were identified in the segment encoding the extracellular ligand-binding domain of the receptor. Eight independent IFN gamma R1-specific mAb's, including seven blocking antibodies, gave recognition patterns that differed between patients, suggesting that different epitopes were altered by the mutations. No specific binding of I-125-IFN-gamma to cells was observed in any patient, however, and the cells failed to respond to IFN-gamma. The mutations therefore cause complete IFN gamma R1 deficiency by disrupting the IFN-gamma-binding site without affecting surface expression, The detection of surface IFN gamma R1 molecules by specific antibodies, including blocking antibodies, does not exclude a diagnosis of complete IFN gamma R1 deficiency.