RESIDENT SKIN CELLS AND THEIR CYTOKINES IN AUTOIMMUNITY

已经认识到，大多数自身免疫性疾病具有多方面的 病因学 免疫过程失调，以及局部 相关器官系统内的环境似乎有助于 发病机制 使用针对表皮细胞的小鼠模型 同种异体抗原，Skn，我们可以通过过继免疫诱导自身免疫反应。 将CD 4+皮肤免疫淋巴细胞转移至先前免疫抑制的 接受者表达适当的Skn等位基因， 在轻度表皮创伤区域出现病变。 整体 待评估的假设是表皮创伤伴随有 免疫抑制消除了功能失调的皮肤细胞， 皮肤的局部微环境，随后有助于 免疫介导的自身攻击过程。 首先，我们将描述 分子和细胞事件的顺序发生在局部 皮肤源性损伤后的皮肤环境 细胞因子mRNA，并通过将这些细胞因子与 与免疫病理学相关的几个位点修饰的改变： 诱导粘附分子使白细胞迁移到皮肤中， 表皮细胞周期的变化和凋亡的出现 角质形成细胞另一项研究将探讨 常驻皮肤γ/δ T细胞和/或循环淋巴细胞， 似乎是由免疫抑制失活，从而使 接受者易受自动攻击。 这将是决定 通过将正常皮肤细胞和/或淋巴细胞沿着与Skn- 接受者将接受免疫细胞评估以降低发病率 皮肤病变和改变皮肤细胞因子谱。 此外我们 将通过以下方式鉴定损伤皮肤内表达细胞因子的细胞： 使用原位杂交检测细胞因子mRNA和蛋白质， 免疫组化 因为Skn抗原似乎有一个人类 这种动物模型可以提供必要的信息， 了解免疫和环境致病过程 被认为会导致人类自身免疫性皮肤病。

It has been recognized that most autoimmune diseases have a multifaceted etiology. Both a dysregulated immune process, as well as, the local environment within the involved organ-system appear to contribute to pathogenesis. Using a murine model targeted against the epidermal cell alloantigens, Skn, we can induce an autoimmune response by the adoptive transfer of CD4+ Skn-immune lymphocytes to previously immunosuppressed recipients expressing the appropriate Skn alleles who subsequently develop lesions in areas of mild epidermal trauma. The overall hypothesis to be evaluated is that epidermal trauma concomitant with immunosuppression elicits dysfunctional resident skin cells which alter the local microenvironment of the skin, subsequently contributing to the immune-mediated autoaggressive processes. First, we will characterize the sequence of molecular and cellular events that occur in the local skin environment after superficial trauma by analyzing skin-derived cytokine mRNA using PCR and by correlating those cytokines found with several site-modified alterations associated with immunopathology: the induction of adhesion molecules for leukocyte migration into the skin, changes in epidermal cell cycling, and appearance of apoptotic keratinocytes. Another study will address autoregulatory properties of resident skin gamma/delta T-cells and/or circulating lymphocytes, which appear to be inactivated by immunosuppression thereby rendering the recipient susceptible to autoaggressive attack. This will be determined by cotransfer of normal skin cells and/or lymphocytes along with Skn- immune cells to recipients who will be evaluated for reduced incidence of skin lesions and for altered skin cytokine profiles. In addition we will identify the cells expressing cytokines within lesional skin by detection of cytokine mRNA and protein using in situ hybridization and immunohistochemistry. In that Skn antigen appears to have a human counterpart, this animal model can provide information essential for understanding both the immune and the environmental pathogenic processes thought to contribute to human autoimmune dermatoses.