Pathogenesis of cutaneous lupus erythematosus

描述（由申请人提供）： 系统性红斑狼疮（SLE）是一种以T细胞异常活化和高水平自身抗体及肾脏、皮肤等多器官组织损害为特征的自身免疫性疾病。其病因尚不清楚。皮肤表现在SLE患者中很常见，由于对相关致病机制的了解有限，因此没有特异性治疗。皮肤损伤也存在于狼疮倾向的MRL/lpr小鼠中。我们最近观察到，通过肿瘤坏死因子（TNF）受体1的信号参与表达的狼疮易感小鼠的皮肤损伤和人或小鼠狼疮血清诱导皮肤炎症后，皮内注射在正常小鼠。我们建议，狼疮血清的成分涉及TNF受体1启动皮肤炎症过程。我们建议确定SLE血清诱导的皮肤炎症的性质;确定SLE血清中负责皮肤炎症的组分;并确定TNFR 1在SLE血清诱导的皮肤炎症发展中的作用。我们的研究将使用转基因动物和新型TNF受体信号传导抑制剂来阐明SLE皮肤损伤的发病机制，并提出新的局部治疗方法。在完成所提出的研究后，将提出TNF受体信号传导的特异性抑制剂作为自身免疫性皮肤病变的新疗法。 公共卫生相关性：皮肤表现在SLE患者中很常见，由于对相关致病机制的了解有限，因此没有特异性治疗。在完成所提出的研究后，将提出TNF受体信号传导的特异性抑制剂作为自身免疫性皮肤病变的新疗法。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormal T cell activation and high levels of autoantibody and multi-organ tissue damage including kidney and skin. Its etiology remains unclear. Skin manifestations are frequent in patients with SLE and because of limited understanding of the involved pathogenic mechanisms there is no specific treatment. Skin injury also exists in the lupus-prone MRL/lpr mice. We have recently observed that signaling through tumor necrosis factor (TNF) receptor 1 is involved in the expression of skin injury in the lupus-prone mice and that human or murine lupus serum induces skin inflammation following intradermal injection in normal mice. We propose that components of lupus serum involve TNF receptor 1 to initiate a skin inflammatory process. We propose to determine the nature of SLE serum-induced skin inflammation; identify the component(s) of SLE serum responsible for the skin inflammation; and determine the role of TNFR1 in the development of SLE serum-induced skin inflammation. Our studies will use genetically modified animals and novel TNF receptor signaling inhibitors to shed light on the pathogenesis of skin injury in SLE and suggest novel local therapeutics. Upon the completion of the proposed studies specific inhibitors of TNF receptor signaling will be proposed as novel therapeutics of autoimmune skin lesions. PUBLIC HEALTH RELEVANCE: Skin manifestations are frequent in patients with SLE and because of limited understanding of the involved pathogenic mechanisms there is no specific treatment. Upon the completion of the proposed studies specific inhibitors of TNF receptor signaling will be proposed as novel therapeutics of autoimmune skin lesions.