Cellular and humoral immune mechanisms underlying neurovascular dysfunction in autoimmune encephalitis

自身免疫性脑炎神经血管功能障碍的细胞和体液免疫机制

• 批准号: 9288055
• 负责人: Dritan Agalliu
• 金额: $ 35.17万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-08 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288055
• 关键词: Acute; Adenoidal structure; Adoptive Transfer; Antibodies; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmune encephalitis; Axon; Bacterial Infections; Basal Ganglia; Behavior; Behavioral; Behavioral Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain region; CD4 Positive T Lymphocytes; Cells; Cellular Structures; Cerebrovascular system; Child; Childhood; Corpus striatum structure; Cues; Defect; Deposition; Development; Diagnosis; Disease; Dopamine; Dopamine Receptor; Dorsal; Encephalitis; Extravasation; Functional disorder; Future; Genetic; Globus Pallidus; Human; Immune; Immune response; Impairment; Infection; Infectious Agent; Interleukin-17; Intravenous; Light; Link; Lymphocyte; Lymphoid Tissue; Measures; Mediating; Mental Health; Mental disorders; Motor; Motor Activity; Movement; Movement Disorders; Multiple Sclerosis; Mus; Mutant Strains Mice; Neurons; Neurophysiology - biologic function; Nose; Olfactory Nerve; Olfactory Pathways; Output; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Play; Presynaptic Terminals; Production; Proteins; Public Health; Rodent; Role; Route; Sensory; Slice; Smell Perception; Streptococcal Infections; Streptococcus pyogenes; Substantia nigra structure; Sydenham Chorea; Symptoms; Synapses; Synaptic Transmission; Syndrome; T-Lymphocyte; Testing; Therapeutic; Tissues; adaptive immune response; adaptive immunity; chemokine; experimental study; in vivo two-photon imaging; inhibitor/antagonist; loss of function; migration; motor deficit; neural circuit; neuroinflammation; neuronal circuitry; neuropsychiatric disorder; neurovascular; neurovascular injury; novel; olfactory bulb; olfactory sensory neurons; prevent; receptor; trafficking

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.

项目摘要 抗神经元受体和突触蛋白的抗体与引起运动或精神障碍的脑炎综合征有关。虽然自身抗体的鉴定促进了这些疾病中的一些的诊断和治疗，但是自身抗体进入大脑并引起神经血管病理的机制仍然不清楚。儿童A组链球菌（GAS）感染与基底节脑炎（BGE）相关，基底节脑炎（BGE）产生运动[Sydenham舞蹈病（SC）]和精神[链球菌感染相关的儿童自身免疫性神经精神障碍（PANDAS）]症状。体液适应性免疫应答在疾病的发病机制中起着重要作用。在患有SC/PANDAS的急性病儿童的血清中发现了识别多巴胺受体（D1 R/D2 R）的自身抗体。这些自身抗体在输注到啮齿动物脑中或静脉内（i. v.）与破坏血脑屏障（BBB）的药剂联合应用于幼稚受体啮齿动物。我们以前已经表明，鼻内（i.n.）GAS感染途径导致小鼠和人鼻相关淋巴组织中Th 17细胞的产生，Th 17细胞是细胞介导的适应性免疫应答的重要组成部分。GAS特异性Th 17细胞通过嗅觉途径从鼻子迁移到大脑中，它们的存在与抗体的BBB破坏、外渗和大脑沉积相关。我们假设，在多次i.n.感染通过嗅觉神经使用特定的趋化因子线索进入大脑，以诱导BBB破坏，从而使自身抗体能够进入大脑，并与自身抗体一起调节特定神经回路的功能。本研究的主要目的是研究GAS特异性Th 17细胞进入小鼠中枢神经系统的机制。第二个目标是确定Th 17细胞或自身抗体在脑血管病理学（BBB损伤）、神经炎症以及嗅觉和多巴胺能神经回路功能障碍中发挥的特定作用。我们将首先检查GAS特异性T细胞是否通过i.n.或静脉注射途径，通过被动转移到幼稚小鼠体内，并检查它们在大脑中的分布。然后，我们将使用多种GAS感染后免疫细胞运输的药理学抑制剂抑制T细胞迁移到CNS中。我们将分析i.n.的后果。GAS感染对嗅觉回路和气味感知功能以及基底神经节回路和运动行为的影响。最后，我们将确定相对贡献，细胞介导的（Th 17细胞）与体液（自身抗体）的免疫机制发挥在神经血管和多巴胺电路缺陷的气体感染的小鼠的大脑中使用遗传功能丧失的研究和过继转移实验。该项目将揭示与运动或精神疾病相关的脑炎综合征的自身免疫介导机制，并有助于开发未来治疗这些疾病的疗法。