Cellular and humoral immune mechanisms underlying neurovascular dysfunction in autoimmune encephalitis

项目总结 针对神经元受体和突触蛋白的抗体与导致运动或精神障碍的脑炎综合征有关。虽然自身抗体的识别有助于其中一些疾病的诊断和治疗，但自身抗体进入大脑并导致神经血管病变的机制仍不清楚。儿童中的A组链球菌(GAS)感染与基底节脑炎(BGE)有关，基底节脑炎会产生运动性[Sydenham‘s Chorea(SC)]和精神病学[与链球菌感染相关的儿科自身免疫性神经精神障碍(PANAS)]症状。体液获得性免疫反应在疾病发病机制中起着重要作用。识别多巴胺受体(D1R/D2R)的自身抗体在患有SC/PANAS的急性疾病儿童的血清中被发现。当这些自身抗体被注入啮齿类动物的大脑或静脉注射时，会引起行为异常。与破坏血脑屏障(BBB)的药剂一起转化为幼稚的受体啮齿动物。我们以前已经证明，鼻腔(I.N.)GAS感染途径导致Th17细胞在小鼠和人类的鼻部相关淋巴组织中产生，Th17细胞是细胞介导的适应性免疫反应的重要组成部分。气体特异性Th17细胞通过嗅觉途径从鼻子迁移到大脑，它们的存在与血脑屏障的破坏、渗出和抗体的脑沉积有关。我们假设多个I.N后产生气体特异性Th17细胞。感染利用特定的趋化因子信号通过嗅神经进入大脑，诱导血脑屏障的破坏，从而使自身抗体进入大脑，并与自身抗体一起调节特定神经回路的功能。这项研究的主要目的是检查气体特异性Th17细胞进入小鼠中枢神经系统的机制。第二个目标是确定Th17细胞或自身抗体在脑血管病理(血脑屏障损伤)、神经炎症以及嗅觉和多巴胺能神经回路功能障碍中所起的特殊作用。我们将首先检查GAS特异性T细胞是否通过I.N进入中枢神经系统。或者静脉注射。被动地将它们转移到幼稚的小鼠体内，并检查它们在大脑中的分布。然后，我们将使用药物抑制多种气体感染后免疫细胞的运输，以抑制T细胞向中枢神经系统的迁移。我们将分析I.N的后果。气体感染对嗅觉回路和气味感知的功能以及基底节回路和运动行为的影响。最后，我们将通过遗传功能丧失研究和过继转移实验，确定细胞介导(Th17细胞)和体液(自身抗体)免疫机制在GAS感染小鼠脑内神经血管和多巴胺回路缺陷中所起的相对作用。该项目将阐明与运动或精神障碍相关的脑炎综合征的自身免疫调节机制，并有助于开发未来治疗这些疾病的疗法。

PROJECT SUMMARY Antibodies against neuronal receptors and synaptic proteins are associated with encephalitic syndromes that produce either movement or psychiatric disorders. While the identification of autoantibodies has facilitated diagnosis and treatments for some of these disorders, the mechanisms by which autoantibodies enter the brain and cause neurovascular pathology remain unclear. Group A Streptococcus (GAS) infections in children are associated with basal ganglia encephalitis (BGE) that produces both motor [Sydenham’s chorea (SC)] and psychiatric [Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus infections (PANDAS)] symptoms. The humoral adaptive immune response plays an important role in disease pathogenesis. Autoantibodies that recognize dopamine receptors (D1R/D2R) are found in sera from acutely ill children with SC/PANDAS. These autoantibodies elicit behavioral abnormalities when infused into rodent brains or administered intravenously (i.v.) into naive recipient rodents in conjunction with agents that break down the blood-brain barrier (BBB). We have previously shown that an intranasal (i.n.) route of GAS infection leads to production of Th17 cells, which are an essential component of the cell-mediated adaptive immune response, in the nasal-associated lymphoid tissue of mice and humans. GAS-specific Th17 cells migrate from the nose into the brain via an olfactory route and their presence correlates with BBB breakdown, extravasation and brain deposition of antibodies. We hypothesize that GAS-specific Th17 cells arising after multiple i.n. infections enter the brain via the olfactory nerve using specific chemokine cues, to induce BBB breakdown thus enabling entry of autoantibodies into the brain, and modulate the function of specific neural circuits together with autoantibodies. The primary objective of the study is to examine the mechanisms by which GAS-specific Th17 cells enter the CNS in mice. The second objective is to determine the specific roles that Th17 cells or autoantibodies play in brain vasculature pathology (BBB damage), neuroinflammation and dysfunction of olfactory and dopaminergic neural circuits. We will first examine whether GAS-specific T cells enter the CNS via the i.n. or i.v. route by passively transferring them into naïve mice and examining their distribution into the brain. We will then inhibit migration of T cells into the CNS using pharmacological inhibitors for immune cell trafficking after multiple GAS infections. We will analyze the consequences of i.n. GAS infections for the function of olfactory circuits and odor perception as well as basal ganglia circuitry and motor behaviors. Finally, we will determine the relative contribution that cell-mediated (Th17 cells) versus humoral (autoantibodies) immune mechanisms play in neurovascular and dopamine circuitry deficits in brains of GAS-infected mice using both genetic loss-of-function studies and adoptive transfer experiments. This project will shed light in autoimmune-mediated mechanisms of encephalitic syndromes associated with movement or psychiatric disorders and aid in developing future therapeutics to treat these diseases.