Mechanisms of Ultraviolet Inflammation in Lupus

描述（由申请人提供）：只有一种环境因子始终与皮肤性红斑狼疮（CLE）和系统性红斑狼疮（SLE）有关，那就是紫外线（UV）光。尽管有良好的狼疮小鼠模型，但狼疮小鼠在了解皮肤病的基本发病机制或紫外线（UV）诱导的全身耀斑沉淀方面贡献甚少。研究人员提出，这是由于小鼠较少暴露于UVB，以及小鼠和人类之间浆细胞样树突状细胞（pDC）的根本差异。在这项提议中，研究人员创建了一种新的uvb介导的皮肤病小鼠模型，该模型与pDC浸润和1型干扰素（IFN）特征相关。利用这些中波暴露条件，研究者建议：1)确定中波暴露后pDC的刺激、传感器和作用；2)建立人源化小鼠皮肤LE模型，并确定哪些自身抗体在启动IFN和皮肤炎症中最有效；3)利用表达特定抗体和Toll样受体的小鼠建立UVB介导的疾病恶化的全身小鼠模型，预测这些抗体和Toll样受体将使小鼠对UVB暴露敏感。这些目标的成功完成不仅将告诉我们UVB诱导狼疮的机制，而且还将为研究人员提供试验治疗的有用模型。

DESCRIPTION (provided by applicant): There is only one environmental agent that is consistently linked to cutaneous (CLE) and systemic (SLE) Lupus Erythematosus and that is ultraviolet (UV) light. Despite good mouse models of this disease, lupus mice have contributed little to understanding the basic pathogenesis of skin disease or ultraviolet (UV) light induced-precipitation of systemic flares. The investigators propose that this is due both to lesser exposure of mice to UVB as well as fundamental differences in plasmacytoid dendritic cells (pDC) between mice and humans. In this proposal, the investigators have created a new mouse model of UVB-mediated skin disease that is associated both with pDC infiltration as well as a type 1 interferon (IFN) signature. Using these conditions of UVB exposure, the investigators propose to 1) determine what are the stimuli, sensors and role of pDC following UVB exposure; 2) create a humanized mouse model of cutaneous LE and determine which autoantibodies are most potent in initiating IFN and inflammation in the skin; and 3) develop a systemic mouse model of UVB-mediated disease exacerbation using mice that express defined antibodies and Toll Like Receptors that is predicted will sensitize mice to UVB exposure. Successful completion of these Aims will not only inform us of mechanisms responsible for UVB induced lupus but also provide researchers with useful models for trialing therapies.