Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.
Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.
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DOI：
10.1084/jem.20140280
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发表时间：
2015-09-21
期刊：
影响因子：
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通讯作者：
Boisson-Dupuis S
中科院分区：
文献类型：
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作者：
Kreins AY;Ciancanelli MJ;Okada S;Kong XF;Ramírez-Alejo N;Kilic SS;El Baghdadi J;Nonoyama S;Mahdaviani SA;Ailal F;Bousfiha A;Mansouri D;Nievas E;Ma CS;Rao G;Bernasconi A;Sun Kuehn H;Niemela J;Stoddard J;Deveau P;Cobat A;El Azbaoui S;Sabri A;Lim CK;Sundin M;Avery DT;Halwani R;Grant AV;Boisson B;Bogunovic D;Itan Y;Moncada-Velez M;Martinez-Barricarte R;Migaud M;Deswarte C;Alsina L;Kotlarz D;Klein C;Muller-Fleckenstein I;Fleckenstein B;Cormier-Daire V;Rose-John S;Picard C;Hammarstrom L;Puel A;Al-Muhsen S;Abel L;Chaussabel D;Rosenzweig SD;Minegishi Y;Tangye SG;Bustamante J;Casanova JL;Boisson-Dupuis S
Kreins等报道了一组TYK 2缺陷型患者的鉴定和免疫学表征。常染色体隐性遗传，完全TYK 2缺陷症先前在一名患者（P1）中描述，该患者患有细胞内细菌和病毒感染以及高IgE综合征（HIES）的特征，包括特应性皮炎、高血清IgE水平和葡萄球菌感染。我们从5个家庭和4个不同的种族群体中确定了另外7名TYK 2缺陷患者。这些患者是五个无效突变之一的纯合子，与P1中所见的不同。他们表现出分枝杆菌和/或病毒感染，但没有HIES。所有8名TYK 2缺陷患者均表现出对（a）IL-12和IFN-α/β的细胞应答受损但未消除，分别解释了分枝杆菌和病毒感染;（B）IL-23，循环IL-17+ T细胞比例正常，解释了他们明显缺乏粘膜皮肤念珠菌病;和（c）IL-10，没有明显的临床后果，包括没有炎性肠病。对IL-21、IL-27、IFN-γ、IL-28/29（IFN-λ）和白血病抑制因子（LIF）的细胞应答正常。与P1不同的是，所有7名新发现的TYK 2缺陷患者的白细胞和成纤维细胞对IL-6的反应正常，这可能是这些患者缺乏HIES的原因。外源性野生型TYK 2的表达或内源性TYK 2的沉默不能挽救IL-6低反应性，表明这种表型不是TYK 2基因型的结果。TYK 2缺陷的核心临床表型是分枝杆菌和/或病毒感染，由对IL-12和IFN-α/β的应答受损引起。此外，受损的IL-6反应和HIES似乎不是人类TYK 2缺陷的内在特征。
Kreins et al. report the identification and immunological characterization of a group of TYK2-deficient patients. Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17+ T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.