Impaired IL-7 signaling may explain a case of atypical JAK3-SCID
Impaired IL-7 signaling may explain a case of atypical JAK3-SCID
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DOI：
10.1016/j.cyto.2009.09.009
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发表时间：
2010-02-01
期刊：
影响因子：
3.8
通讯作者：
Asao, Hironobu
中科院分区：
文献类型：
--
作者：
Li, Jun;Nara, Hidetoshi;Asao, Hironobu
Janus激酶3-重症联合免疫缺陷（JAK 3-SCID）是由JAK 3基因的各种突变引起的常染色体隐性免疫缺陷病。典型的JAK 3-SCID的特征在于存在B细胞但不存在T和NK细胞的表型，即T-B +NK-表型，以及通过使用共同γ链（γ c）亚基的细胞因子受体的受损信号传导。一个非典型的JAK 3-SCID病例携带一个JAK 3等位基因的JH 3结构域中的单个谷氨酸到甘氨酸的取代突变（E481 G），和另一个等位基因的JH 3和JH 2结构域中的缺失突变（del 482 -596）。虽然该患者具有不同于典型病例的CD 4（+）T细胞和NK细胞，但CD 4（+）T细胞功能受损。我们在此报告JAK 3-E481 G突变体与野生型JAK 3一样有效地转导IL-2-、IL-4-、IL-15-和IL-21-诱导的信号。然而，该突变体未能通过磷酸化JAK 1、JAK 3或STAT 5来响应IL-7。另一个突变体JAK 3，JAK 3-del 482 -596，是无功能的。因此，受损的IL-7信号可能导致SCID和损害T细胞分化，即使IL-15信号被保留并支持NK细胞发育，如在该患者中。(C)2009爱思唯尔有限公司保留所有权利。
Janus kinase 3-severe combined immunodeficiency (JAK3-SCID) is an autosomal recessive immunodeficiency disease caused by various mutations in the JAK3 gene. Typical JAK3-SCID is characterized by a phenotype in which B cells are present but T and NK cells are not, the T-B+NK- phenotype, and by impaired signaling through cytokine receptors that use the common gamma chain (gamma c) subunit. An atypical JAK3-SCID case carrying a single glutamate to glycine substitution mutation (E481G) in the JH3 domain of one JAK3 allele, and a deletion mutation (del482-596) in the JH3 and JH2 domains of the other allele was reported previously. Although this patient had CD4(+) T cells and NK cells unlike typical cases, the CD4(+) T cells were functionally impaired. We report here that the JAK3-E481G mutant transduced 11-2-, IL-4-, IL-15-, and IL-21-induced signals as efficiently as wild-type JAK3. However, this mutant failed to respond to IL-7 by phosphorylating JAK1,JAK3, or STAT5. The other mutant JAK3, JAK3-del482-596, was non-functional. Thus, an impaired IL-7 signal may cause SCID and compromise T-cell differentiation, even if the IL-15 signal is preserved and supports NK-cell development, as in this patient. (C) 2009 Elsevier Ltd. All rights reserved.