Pathogenesis of cutaneous lupus erythematosus

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，以T细胞异常激活和高水平自身抗体为特征，并伴有包括肾脏和皮肤在内的多器官组织损害。其病因尚不清楚。系统性红斑狼疮患者的皮肤表现常见，由于对其发病机制的了解有限，目前尚无特效治疗方法。狼疮易感的MRL/LPR小鼠也存在皮肤损伤。我们最近观察到，通过肿瘤坏死因子受体1传递的信号参与了狼疮易感小鼠皮肤损伤的表达，而人或小鼠狼疮血清在正常小鼠皮内注射后可诱导皮肤炎症。我们认为狼疮血清的成分与肿瘤坏死因子受体1有关，从而启动了皮肤炎症过程。我们建议确定SLE血清诱导的皮肤炎症的性质；确定SLE血清中与皮肤炎症有关的成分(S)；以及确定肿瘤坏死因子受体1在SLE血清诱导的皮肤炎症中的作用。我们的研究将使用转基因动物和新型肿瘤坏死因子受体信号抑制剂来阐明系统性红斑狼疮皮肤损伤的发病机制，并提出新的局部治疗方法。在拟议的研究完成后，特定的肿瘤坏死因子受体信号抑制剂将被建议作为自身免疫性皮肤损伤的新疗法。 公共卫生相关性：系统性红斑狼疮患者的皮肤表现很常见，由于对相关致病机制的了解有限，目前还没有具体的治疗方法。在拟议的研究完成后，特定的肿瘤坏死因子受体信号抑制剂将被建议作为自身免疫性皮肤损伤的新疗法。

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.