Analysis of the onset mechanisms of Psoriasis Vulgaris using transgenic mice

牛皮癣是一种皮肤炎症性和增生性疾病。一些证据表明银屑病是一种t细胞介导的自身免疫性疾病，但其发病机制尚不清楚。为了研究牛皮癣的发病机制，我们建立了转基因小鼠。各种细胞因子可能通过控制T细胞和角质形成细胞之间的相互作用来协调发病机制。其中，IL6家族细胞因子激活stat3通路。我们提供了stat 3条件敲除小鼠（K5-Cre: Stat3^<flox/->），通过cre-loxP策略释放角质形成细胞中的stat 3。这些突变小鼠表现出自发性溃疡。这种表型不是由于增殖受到抑制，而是由于角质形成细胞的迁移受损。角化细胞中表达的抗原可能是T细胞自身免疫反应的目标。基于这一思路，我们在角蛋白-5启动子（K5-mOVA）下建立了以鸡卵白蛋白（OVA）为模型抗原的转基因小鼠。以MHC II类启动子- mova转基因（II- mova）小鼠为对照。从OVA特异性T细胞（OT-I）转移到K5-mOVA的实验中，表皮表达的抗原组成性地呈献给引流淋巴结的T细胞。T细胞识别抗原，随后增殖，用CFSE方法检测。移植后第5天，携带绿色荧光蛋白（GFP）的T细胞开始向皮肤浸润。这种迁移也诱导了宿主T细胞的非特异性浸润和棘层增生。一些ova特异性TCR和K5-mOVA双转基因小鼠表现出皮肤炎症和结垢，尽管发生率约为5%。现在我们提供移植了TCR转基因骨髓的胸腺（裸）K5-mOVA小鼠，然后移植正常辐照胸腺，观察目前胸腺产生的T细胞是否会诱发皮肤疾病。

Psoriasis is an inflammatory and proliferative disease of the skin. Some evidences indicate that psoriasis is a T-cell mediating autoimmune disease although the pathogenesis is still unclear. To study the onset mechanisms of psoriasis, here we have established transgenic mice.Various cytokines may orchestrate the pathogenesis by controlling the interaction between T cells and keratinoctes. Among them, cytokines of IL6 family activate stat3 pathway. We have provided stat 3 conditional knock out mice (K5-Cre : Stat3^<flox/->) that loose stat 3 in keratinocytes by way of the cre-loxP strategy. These mutant mice have expressed spontaneous ulcers. This phenotype was not due to supressed proliferation but to impaired migration of keratinocytes.Antigens expressed in keratinocytes are presumably targets for the autoimmune response of T cells. Based on this idea, we have established transgenic mice expressing chicken ovalbumin (OVA) as a model antigen under keratin-5 promoter (K5-mOVA). MHC class II promoter-mOVA transgenic (II-mOVA) mice were used as a control. From the experiment with transfer of OVA specific T cells (OT-I) into K5-mOVA, antigens expressed in the epidermis are constitutively presented to T cells in the draining lymph nodes. T cells recognized the antigen, followed by proliferation tha was detected with the CFSE method. T cells carryng green fluorescence protein (GFP) started infiltrating the skin on day 5 after transfer. This migration induced non-specific infiltration of host T cells and acanthosis as well. Some of OVA-specific TCR and K5-mOVA double transgenic mice showed inflammation of the skin and scaling although the incidence was around 5 percent. Now we are providing athymic (nude) K5-mOVA mice having been transplanted with TCR transgenic bone marrow, followed by transplantation with normal irradiated thymus to see whether T cells currently generated from the thymus induce skin diseas or not.