Analysis of the onset mechanisms of Psoriasis Vulgaris using transgenic mice

银屑病是一种炎症性和增生性皮肤疾病。有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。为了研究银屑病的发病机制，我们建立了转基因小鼠，多种细胞因子可能通过控制T细胞与角质形成细胞之间的相互作用而参与银屑病的发病机制。其中，IL 6家族的细胞因子激活stat 3通路。我们已经提供了stat 3条件性敲除小鼠（K5-Cre：Stat 3 ^<flox/->），其通过cre-loxP策略在角质形成细胞中释放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抑制，而是由于角质形成细胞的迁移受损。角质形成细胞中表达的抗原可能是T细胞自身免疫反应的靶点。基于这一想法，我们建立了在角蛋白-5启动子下表达鸡卵清蛋白（OVA）作为模型抗原的转基因小鼠（K5-mOVA）。使用MHC II类启动子-mOVA转基因（II-mOVA）小鼠作为对照。根据将OVA特异性T细胞（OT-I）转移到K5-mOVA中的实验，表皮中表达的抗原组成型呈递给引流淋巴结中的T细胞。CFSE法检测T细胞识别抗原后的增殖。在转移后第5天，携带绿色荧光蛋白（GFP）的T细胞开始浸润皮肤。这种迁移也诱导宿主T细胞的非特异性浸润和棘皮病。一些OVA特异性TCR和K5-mOVA双转基因小鼠出现皮肤炎症和鳞屑，尽管发病率约为5%。现在，我们提供了无胸腺（裸）K5-mOVA小鼠，其已经移植了TCR转基因骨髓，随后移植了正常的辐射胸腺，以观察目前从胸腺产生的T细胞是否诱发皮肤病。

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.