The role of TWEAK and Fn14 in the Pathogenesis and Treatment of Neuropsychiatric

描述（由申请人提供）：系统性红斑狼疮（SLE）是一种全身性自身免疫性疾病，神经精神疾病的发病率很高。神经精神系统性红斑狼疮（NPSLE）的体征和症状是狼疮患者最早和最常见的表现之一，并且可以独立于非神经系统疾病发生。在MRL/lpr品系（一种常用的鼠狼疮模型）中，在自身抗体滴度增加和其他主要器官受累之前，与重度抑郁和认知受损一致的行为变化在幼龄动物中也很明显。这些和其他研究表明，NPSLE确实是一种原发性疾病的表现。然而，尽管NPSLE的患病率高，预后差，但其发病机制尚不清楚，最佳治疗仍不清楚。之前的研究主要集中在潜在的病因因素上，例如自身抗体和神经退行性变，这些因素通常在系统性红斑狼疮发病后相对较晚才变得明显。这些因素不能充分解释狼疮小鼠或许多患者中观察到的NPSLE的早期发作。在早期CNS功能障碍的假定调节剂中，细胞因子可以通过一系列不同的机制直接和间接地促进CNS不良结果。这些包括对自身抗体的影响、增加细胞因子和其他炎性介质的分泌、血脑屏障（BBB）完整性的丧失以及细胞因子的改变。 神经递质代谢 TNF超家族成员在SLE的发病机制中是重要的。TWEAK是该细胞因子超家族的分泌成员，对多种细胞类型具有多效性作用，包括促进炎症和对细胞存活和凋亡的环境依赖性作用。TWEAK受体Fn 14在星形胶质细胞、小胶质细胞、脑微血管内皮细胞和神经元中表达。此外，TWEAK诱导已知在NPSLE中发挥作用的其他炎性细胞因子的释放。最近，我们发现Fn 14缺陷型MRL/lpr狼疮小鼠比Fn 14充足型MRL/lpr同窝小鼠显示出显著更少的抑郁和认知异常，而人NPSLE与CSF中的高TWEAK水平相关。我们的初步研究强烈支持以下假设：1）TWEAK在NPSLE的病因学中起主要作用; 2）TWEAK阻断可能是治疗神经精神疾病的新方法。在这个提议中，我们将确认TWEAK在NPSLE发病机制中的作用，研究TWEAK信号传导诱导狼疮神经行为异常的机制，并研究TWEAK抑制治疗NPSLE表现的治疗潜力。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a high incidence of neuropsychiatric involvement. Signs and symptoms of neuropsychiatric SLE (NPSLE) are among the earliest and most common manifestations in lupus patients, and can occur independently of non-neurologic disease. In the MRL/lpr strain as well, a commonly used murine lupus model, behavioral changes consistent with severe depression and impaired cognition are evident in young animals before increased autoantibody titers and other major organ involvement. These and other studies indicate that NPSLE is indeed a primary disease manifestation. Nevertheless, despite the high prevalence of NPSLE and its poor prognosis, the pathogenesis is not well understood and optimal treatment is still unclear. Previous studies have largely focused on potential etiological factors such as autoantibodies and neurodegeneration that often become apparent only relatively late after onset of SLE. These factors do not adequately explain the early onset of NPSLE observed in lupus mice or in many patients. Among putative regulators of early CNS dysfunction, cytokines can both directly and indirectly promote negative CNS outcomes via a range of different mechanisms. These include effects on autoantibodies, increasing secretion of cytokines and other inflammatory mediators, loss of integrity of the blood brain barrier (BBB), and alteration of neurotransmitter metabolism. Members of the TNF superfamily are important in the pathogenesis of SLE. TWEAK is a secreted member of this cytokine superfamily, with pleotropic effects on multiple cell types, including promotion of inflammation and context-dependent effects on cell survival and apoptosis. The TWEAK receptor, Fn14, is expressed in astrocytes, microglia, brain microvascular endothelial cells, and neurons. Furthermore, TWEAK induces the release of other inflammatory cytokines known to play a role in NPSLE. Recently, we found that Fn14 deficient MRL/lpr lupus mice display significantly less depression and cognitive abnormalities than Fn14 sufficient MRL/lpr littermates, while human NPSLE is associated with high TWEAK levels in the CSF. Our preliminary studies strongly support the hypotheses that 1) TWEAK plays a major role in the etiology of NPSLE; 2) TWEAK blockade may be a novel approach for the treatment of neuropsychiatric disease. In this proposal, we will confirm the role of TWEAK in the pathogenesis of NPSLE, examine the mechanisms by which TWEAK signaling induces neurobehavioral abnormalities in lupus, and study the therapeutic potential of TWEAK inhibition for treating manifestations of NPSLE.