CNS Lupus: Mechanistic Dissection

描述（由申请人提供）：神经精神（NP）狼疮是SLE发病率和死亡率的主要贡献者。虽然狼疮中枢神经系统（CMS）功能障碍的病因还不完全清楚，但最近的工作表明，抗双链DNA抗体可通过与N-甲基-D-天冬氨酸（NMDA）受体的交叉反应性诱导正常小鼠脑损伤。使用肽诱导的SLE小鼠模型的更近期证据表明，此类自身抗体进入CNS发生在血脑屏障（BBB）破裂后。在初步研究中，TLR激活导致BBB开放，在SLE的MRL小鼠模型中，脑中免疫球蛋白（IG）沉积增强。这些发现提示了这样的假设，即BBB破坏是狼疮中IG进入脑的可能机制，并且Toll样受体（TLR）的刺激启动和/或促进这种破坏，导致IG沉积和随后的CNS损伤。这一假设得到以下证据的支持：TLR参与，包括TLR 9，以及最可能的TLR 8，7和/或8，在狼疮的疾病起始和/或疾病传播中起关键作用。该提案的目的是探索TLR激活在CNS狼疮中的作用，特别是可能参与疾病发生的关键TLR，使用MRL小鼠和在选定TLR中具有遗传缺陷的MRL小鼠。

DESCRIPTION (provided by applicant): Neuropsychiatric (NP) lupus is a major contributor to the morbidity and mortality in SLE. Although the etiology of central nervous system (CMS) dysfunction in lupus is incompletely understood, recent work has shown that anti-double stranded DNA antibodies can induce brain injury in normal mice via cross-reactivity with N-methyl-D-aspartate (NMDA) receptors with neuronal injury. More recent evidence using a peptide-induced murine model of SLE indicates that entry of such autoantibodies into the CNS occurs upon breach of the blood-brain barrier (BBB). In preliminary studies, TLR activation caused opening of the BBB with enhanced immunoglobulin (Ig) deposition in the brain in the MRL mouse model of SLE. These findings suggest the hypothesis that BBB disruption is the likely mechanism for Ig entry into the brain in lupus, and that stimulation of Toll-like receptors (TLRs) initiates and/or promotes this disruption, leading to deposition of Ig and subsequent CNS injury. This hypothesis is supported by evidence that TLR engagement, including TLR9, and most likely TLRsS, 7 and/or 8, plays a critical role in disease initiation and/or disease propagation in lupus. The goal of this proposal is to explore the role of TLR activation in CNS lupus, and in particular key TLRs that are likely involved in disease genesis using MRL mice and MRL mice with genetic deficiencies in selected TLRs.