Anti-NMDA receptor antibodies in adult brain dsyfunction & fetal brain developmen

描述(由申请人提供)：这项提议是继续研究抗DNA抗体的一个子集，称为DNRAb，它与N-甲基-D-天冬氨酸受体交叉反应，并有助于神经精神病学SLE(NPSLE)。该计划的前5年提供了第一个抗体介导的NPSLE损伤的机制模型，在小鼠身上证明了DNRAb可以导致认知和行为障碍。NPSLE患者脑脊液和脑组织中存在DNRAb，脑脊液中的DNRAb滴度与症状严重程度相关。我们还开发了一种抗体结合的小分子竞争性抑制物。我们建议在未来5年内开发一种可逆性脑功能损害和固定性功能损害的模型。在项目1中，我们将确定抗体浓度和NMDAR亚基组成对可逆和不可逆损伤的贡献。我们将测试神经元丢失是否是固定损伤的先决条件，或者DNRAbs介导的效应是否会在缺乏神经元的情况下导致持续性神经元功能障碍。我们将探索吞噬死亡神经元的小胶质细胞的激活及其在维持神经元功能障碍中的作用。 在项目2中，我们将探索神经成像的潜力，以区分DNRAb介导的损害与NPSLE中的其他侮辱。我们将通过成像和神经精神病学测试来探索大脑功能障碍的进展。我们将开发一种成像指标，作为NPSLE和DNRAb阻断试验的结果衡量标准。 在项目3中，我们将开始探索DNRAb对不受血脑屏障保护的垂体细胞的影响，以及DNRAb增加催乳素产生的能力。由于20%到25%的SLE患者中催乳素水平较高，而且催乳素导致更具自身反应性的B细胞系，我们将测试诱骗抗原是否可以导致血清催乳素降低，并可能导致自身反应性减弱。 这些研究源于大量已发表的初步数据，并将继续为非国家可持续发展教育制定范例。小鼠和患者的协同研究丰富了我们对发病机制的理解，验证了我们的小鼠模型，并为未来治疗药物的测试提供了机会。

DESCRIPTION (provided by applicant): This proposal is to continue studies of a subset of anti-DNA antibodies, termed DNRAbs, that cross-react with the N-methyl-D-aspartate receptor and contribute to neuropsychiatric SLE (NPSLE). The first 5 years of the Program provided the first mechanistic model for antibody mediated injury in NPSLE, demonstrating in mice that DNRAbs could cause both cognitive and behavioral impairments. DNRAbs are present in cerebrospinal fluid (CSF) and brain tissue of patients with NPSLE and titers in CSF correlate with symptom severity. We have also developed a small molecule competitive inhibitor of antibody binding. We propose over the next 5 years to develop a model for reversible functional brain impairment as well as fixed functional impairment. In Project 1, we will determine the contribution of antibody concentration and NMDAR subunit composition to reversible and irreversible injury. We will test whether neuron loss is a prerequisite for fixed impairment or whether DNRAbs- mediated effects can lead to persistent neuronal dysfunction in its absence. We will explore the activation of microglial cells that have ingested dead neurons and their role in maintaining neuronal dysfunction. In Project 2, we will explore the potential for neuroimaging to distinguish DNRAb-mediated damage from other insults in NPSLE. We will explore progression of brain dysfunction through imaging and neuropsychiatric testing. We will develop an imaging metric to use as an outcome measure in trials of NPSLE and DNRAb blockade. In Project 3, we will begin to explore effects of DNRAbs on pituitary cells not protected by a blood brain barrier and the capacity of DNRAbs to augment prolactin production. Because prolactin levels are high in 20 to 25% of SLE patients and because prolactin leads to a more autoreactive B cell repertoire, we will test whether decoy antigens can lead to reduced serum prolactin and might perhaps lead to diminished autoreactivity. These studies derive from extensive published and preliminary data and will continue to develop paradigms for NPSLE. The coordinated study of mice and patients enriches our understanding of pathogenesis, validates our mouse model, and provides an opportunity for future testing of therapeutic agents.