CNS Lupus: Mechanistic Dissection

描述(由申请人提供)：神经精神病学(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，但最近的研究表明，抗双链DNA抗体可以通过与N-甲基-D-天冬氨酸(NMDA)受体的交叉反应导致神经元损伤，从而导致正常小鼠脑损伤。最近使用多肽诱导的系统性红斑狼疮小鼠模型的证据表明，当血脑屏障(BBB)被打破时，这种自身抗体进入中枢神经系统。在初步研究中，在系统性红斑狼疮MRL小鼠模型中，TLR激活导致血脑屏障开放，免疫球蛋白(Ig)在大脑中沉积增加。这些发现表明，血脑屏障的破坏可能是Ig进入狼疮脑的可能机制，刺激Toll样受体(TLRs)启动和/或促进这种破坏，导致Ig沉积和随后的中枢神经系统损伤。这一假说得到了以下证据的支持：TLR参与，包括TLR9，以及最有可能的TLRs，7和/或8，在狼疮的疾病起始和/或疾病传播中起着关键作用。这项建议的目的是探索TLR激活在中枢神经系统狼疮中的作用，特别是可能参与疾病发生的关键TLR，使用MRL小鼠和具有所选TLR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.