An Atopic Dermatitis-Like Skin Disease with Hyper-IgE-emia Develops in Mice Carrying a Spontaneous Recessive Point Mutation in the Traf3ip2 (Act1/CIKS) Gene
An Atopic Dermatitis-Like Skin Disease with Hyper-IgE-emia Develops in Mice Carrying a Spontaneous Recessive Point Mutation in the Traf3ip2 (Act1/CIKS) Gene
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DOI：
10.4049/jimmunol.0900694
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发表时间：
2010-08-15
影响因子：
4.4
通讯作者：
Yonekawa, Hiromichi
中科院分区：
文献类型：
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作者：
Matsushima, Yoshibumi;Kikkawa, Yoshiaki;Yonekawa, Hiromichi
自发突变小鼠，表现出高水平的血清IgE和特应性皮炎（AD）样皮肤病被发现在一个殖民地的KOR近交系，来自日本野生小鼠。高IgE血症和皮炎（BALB/c × KOR突变）N-2小鼠之间没有分离，这表明该突变可归因于一个单一的隐性基因座，我们将其命名为adjm（日本小鼠的特应性皮炎）。所有四个adjm同源株在不同的遗传背景，高IgE血症和皮炎，虽然疾病的严重程度不同菌株。使用（BALB/c x KOR-adjm/adjm）N-2小鼠的连锁分析将潜在的adjm基因座限制在10号染色体上D10 Stm 216和D10 Stm 238之间的940 kb。位于该区域的基因的序列分析显示，编码人TNFR相关因子3相互作用蛋白2的小鼠同源物的基因AI 429613 TRAF 3 IP 2蛋白（以前称为NF-κ B激活剂1/与I κ B激酶和应激活化蛋白激酶/Jun激酶的连接），携带导致氨基酸位置214处谷氨酰胺的终止密码子被取代的单点突变。TRAF 3 IP 2已显示在上皮细胞和B细胞中由TNFR超家族成员CD 40和B细胞活化因子介导的信号传导途径中以及在IL-17介导的信号传导途径中作为接头蛋白发挥作用。我们的研究结果表明，TRAF 3 IP 2蛋白的功能障碍通过B细胞中的CD 40和B细胞活化因子介导的途径引起高IgE血症，并通过IL-17介导的途径引起皮肤炎症。这项研究表明TRAF 3 IP 2蛋白在AD中起重要作用，并建议该蛋白作为治疗AD的治疗靶点。免疫学杂志，2010，185：2340-2349。
Spontaneous mutant mice that showed high levels of serum IgE and an atopic dermatitis (AD)-like skin disease were found in a colony of the KOR inbred strain that was derived from Japanese wild mice. No segregation was observed between hyper-IgE-emia and dermatitis in (BALB/c x KOR mutant) N-2 mice, suggesting that the mutation can be attributed to a single recessive locus, which we designated adjm (atopic dermatitis from Japanese mice). All four adjm congenic strains in different genetic backgrounds showed both hyper-IgE-emia and dermatitis, although the disease severity varied among strains. Linkage analysis using (BALB/c x KOR-adjm/adjm) N-2 mice restricted the potential adjm locus to the 940 kb between D10Stm216 and D10Stm238 on chromosome 10. Sequence analysis of genes located in this region revealed that the gene AI429613, which encodes the mouse homologue of the human TNFR-associated factor 3-interacting protein 2 (TRAF3IP2) protein (formerly known as NF-kappa B activator 1/connection to I kappa B kinase and stress-activated protein kinase/Jun kinase), carried a single point mutation leading to the substitution of a stop codon for glutamine at amino acid position 214. TRAF3IP2 has been shown to function as an adaptor protein in signaling pathways mediated by the TNFR superfamily members CD40 and B cell-activating factor in epithelial cells and B cells as well as in the IL-17-mediated signaling pathway. Our results suggest that malfunction of the TRAF3IP2 protein causes hyper-IgE-emia through the CD40- and B cell-activating factor-mediated pathway in B cells and causes skin inflammation through the IL-17-mediated pathway. This study demonstrates that the TRAF3IP2 protein plays an important role in AD and suggests the protein as a therapeutic target to treat AD. The Journal of Immunology, 2010, 185: 2340-2349.