The disease model of the new discovery atopic dermatitis mouse and the positional cloning of the responsibility gene

特应性皮炎(AD)是一种遗传性瘙痒性慢性复发性湿疹皮炎，由遗传因素和环境因素的复杂相互作用引起，常与血清IgE水平升高有关。虽然人们已经做出了很多努力来阐明其发病机制，但仍然难以捉摸，也没有确定相关的基因。因此，建立遗传性阿尔茨海默病的动物模型是一个紧迫的问题：我们报道了一种新的小鼠模型的建立，命名为日本特应性皮炎(NAD)小鼠，并定位了责任基因1。NAD小鼠来源于近交系小鼠KOR小鼠，其表型为常染色体隐性遗传。SPF环境下饲养的NAD小鼠在4~5周龄时首次出现眼睑皮肤水肿性改变，并伴有血清IgE升高。水肿扩散到面部其他部位，头部和前脚；受影响的皮肤被肥大细胞渗透，最终发展为侵蚀、溃疡和毛发脱落。结论：1.这些临床特征与NC小鼠不同，AD的另一种小鼠模型：繁育试验显示NAD小鼠和NC小鼠的等位基因不同。对NAD与BALB/c的F2连锁分析表明，该致病基因位于第10染色体上，与D10Mit53和D10Mit109相近。有趣的是，人类染色体6q22-23上的同线区域含有INFgR和TNFAIP3基因，它们可能是AD的致病基因。对NAD小鼠的进一步研究将有助于阐明ADD的发病机制。在近交系小鼠品系KOR的群体中发现了一个新的突变体，它显示了人类特应性皮炎样表型。定位克隆显示，人Traf3ip2蛋白的小鼠同源物携带单点突变，导致^214谷氨酰胺取代无意义密码子。这表明Traf3ip2在上皮细胞和B细胞的动态平衡中起着重要的作用

Atopic dermatitis (AD) is a hereditary pruritic chronic relapsing eczematous dermatitis resulted from complex interactions between genetic and environmental factors, and is frequently associated with elevated levels of serum IgE. While much effort was made to elucidate the pathogenesis, it remains to be elusive and responsible genes are not identified. Hence, establishment of animal models for hereditary AD is an urgent issue: We here report the establishment of a new mouse model, named Nippon atopic dermatitis (NAD) mice, and the mapping of responsible gene.1. NAD mice were derived from KOR mice, an inbred strain of Mus musclus molossinus, and their phenotype was transmitted in an autosomal recessive manner. The phenotype of NAD mice kept in SPF environment first appeared as edematous skin change at eyelids at the age of 4-5 weeks with elevation of serum IgE. The edema spread to other face regions, head and forefoot ; the affected skin is infiltrated with mast cell and eventually developed erosion, ulceration and loss of hairs. These clinical characteristics are distinct from those of NC mice, another mouse model of AD : Breeding test revealed that the alleles of NAD and NC mice are different.2. Linkage analysis using F2 between NAD and BALB/c revealed that the responsible gene localizes on chromosome 10 close to D10Mit53 and D10Mit109. Interestingly, human chromosomal region syntenic ton this region, 6q22-23, contains the INFgR and TNFaIP3 genes, which may be responsible genes for AD. Further study of NAD mice will contribute to elucidate the pathogenesis of AD.3. A novel mutant that showed human atopic dermatitis-like phenotypes was found in a colony of the inbred mouse strain KOR. Positional cloning revealed that the mouse homologue of human Traf3ip2 protein, carried a single point mutation leading to the substitution of^214glutamine for nonsense codon. This indicated that Traf3ip2 played an important role in the homeostasis of epithelial cells and B cells