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因素。虽然狼疮中枢神经系统（CMS）功能障碍的病因尚不完全清楚，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）受体的交叉反应诱导正常小鼠脑损伤。最近使用肽诱导的SLE小鼠模型的证据表明，这种自身抗体进入中枢神经系统发生在血脑屏障（BBB）的破坏。在初步研究中，在SLE MRL小鼠模型中，TLR激活导致血脑屏障打开并增强免疫球蛋白（Ig）沉积。这些发现表明，血脑屏障破坏可能是狼疮患者Ig进入大脑的机制，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。这一假设得到了TLR参与的证据的支持，包括TLR9，以及最有可能的tlr7和/或8，在狼疮的疾病发生和/或疾病传播中起关键作用。本研究的目的是利用MRL小鼠和TLR基因缺陷的MRL小鼠，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。

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.