Anti-interneuron antibodies in rapid-onset pediatric OCD: clinical generalization and target identification

快速发作的儿科强迫症中的抗中间神经元抗体：临床概括和靶标识别

• 批准号: 10530955
• 负责人: Christopher John Pittenger
• 金额: $ 85.29万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530955
• 关键词: Acute; Affect; Antibodies; Antibody Formation; Antigens; Anxiety; Autoantibodies; Autoimmune; Autoimmunity; Autopsy; B-Lymphocytes; Basal Ganglia; Behavior; Behavioral; Binding; Biological Assay; Brain; Characteristics; Child; Childhood; Chorea; Clinic; Clinical; Coin; Consensus; Corpus striatum structure; Country; Data; Development; Discrimination; Enzyme-Linked Immunosorbent Assay; Epitopes; Etiology; Exhibits; Functional disorder; Gilles de la Tourette syndrome; Hand; Human; Immune; Immunofluorescence Immunologic; Immunoglobulin G; In Vitro; Individual; Infection; Inflammation; Interneurons; Lead; Literature; Medial; Methodology; Modeling; Molecular Conformation; Molecular Target; Morbidity - disease rate; Mus; Neuroimmune; Neurologic; Neurons; Noise; Obsessive-Compulsive Disorder; Pathogenicity; Pathology; Patients; Pattern; Peripheral Blood Mononuclear Cell; Population; Process; Production; Prosencephalon; Proteins; Recombinants; Sampling; Separation Anxiety; Serum; Signal Transduction; Streptococcal Infections; Streptococcus; Surface; Sydenham Chorea; Symptoms; Syndrome; Techniques; Testing; Time; Tissues; Work; Yeasts; base; beta catenin; brain tissue; cholinergic; cholinergic neuron; clinical subtypes; cohort; comorbidity; coronavirus disease; diagnostic tool; disease classification; food restriction; immune function; immunomodulatory therapies; immunoreaction; innovation; medical specialties; monoclonal antibody production; neuroinflammation; neuropsychiatric disorder; neuropsychiatry; novel; novel diagnostics; novel strategies; pathogenic autoantibodies; putamen; relating to nervous system; repetitive behavior; screening; symposium; symptomatic improvement; symptomatology; treatment center; urinary

ABSTRACT Obsessive-compulsive disorder affects 1-4% of children and produces substantial morbidity and disruption of normal development. In some children, rapid onset and a characteristic set of accompanying symptoms suggest a unique pathophysiology; this has been termed ‘Pediatric Acute-Onset Neuropsychiatric Syndrome’, or PANS. PANS onset often occurs following an infectious illness, suggesting that some cases of rapid-onset pediatric OCD are triggered by neuroinflammatory processes. Specifically, it has been proposed that certain infections can, in a susceptible child, lead to the production of autoantibodies that cross-react with brain epitopes and lead to basal ganglia inflammation, and thereby to OCD symptomatology. The targets of these autoantibodies remain unclear, and the hypothesis of autoimmunity as a cause of PANS is controversial. In recent work we used a novel approach to characterize the binding of antibodies from children with PANDAS (Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus), a form of PANS in which symptoms are temporally associated with Streptococcal infection, to brain tissue. We have discovered, and multiply replicated, that IgG from children with PANDAS binds to specific interneurons within the caudate- putamen: the cholinergic interneurons, or CINs. CIN binding by PANDAS-associated IgG reduces their activity in two ex vivo assays. Both effects – IgG binding to CINs and reduction in their activity – are lost in children who exhibit symptomatic improvement following immune-modulating therapy. CIN pathology has been independently associated with Tourette syndrome, and we have found CIN disruption to lead to repetitive behavioral pathology in mice. These convergent findings give inherent plausibility to the novel hypothesis that antibody binding to and consequent inhibition of CINs contributes to the pathophysiology of PANDAS. Here we test and extend this analysis in critical ways. First, we will use the novel REAP screening methodology, based on yeast surface display of >3000 human proteins in their native conformation, to identify candidate antibody targets. We will validate these candidates by testing whether antibodies against them can bind to and inhibit CINs; pilot work has already identified three such candidates, and new data confirm CIN binding by one of them. Second, by examining sera from >350 children drawn from specialty treatment centers across the country, we will test whether CIN binding is specific to PANDAS or is seen more generally in PANS, or even in non-PANS OCD. Finally, we will culture individual B cells from selected children with PANDAS and PANS and will screen them for production of monoclonal antibodies against identified targets. This will, for the first time, allow us to identify and clone specific candidate autoantibodies associated with these conditions. Together, these innovative studies have the potential to fundamentally advance our understanding of PANS and PANDAS, paving the way for a pathophysiology-based nosology and for the development of new diagnostic tools and treatments.

摘要 强迫症影响1-4%的儿童，并产生相当大的发病率和中断的 正常发展。在一些儿童中，快速发作和一组特征性的伴随症状 提示一种独特的病理生理学;这被称为“小儿急性发作神经精神综合征”， 或PANS。PANS的发病通常发生在感染性疾病之后，这表明一些快速发病的病例 儿童强迫症是由神经炎症过程引发的。具体而言，有人提出， 在易感儿童中，感染可导致自身抗体的产生， 表位，并导致基底神经节炎症，从而导致强迫症。这些目标 自身抗体仍不清楚，自身免疫作为PANS病因的假说也存在争议。 在最近的工作中，我们使用了一种新的方法来表征来自PANDAS儿童的抗体的结合。 （链球菌相关的儿童自身免疫性神经精神障碍），PANS的一种形式，其中 症状与链球菌感染暂时相关，并转移到脑组织。我们发现， 多重复制，来自PANDAS儿童的IgG与尾状核内的特定中间神经元结合， 壳核：胆碱能中间神经元，或称CIN。通过PANDAS相关IgG结合CIN降低其活性 在两个离体测定中。这两种效应-- IgG与CIN的结合及其活性的降低--在儿童中均丧失 在免疫调节治疗后表现出症状改善的患者。CIN病理学一直是 独立与Tourette综合征相关，我们发现CIN中断导致重复性 小鼠的行为病理学这些趋同的发现为新的假设提供了内在的合理性， 抗体与CIN的结合和随后的抑制有助于PANDAS的病理生理学。 在这里，我们以批判的方式测试和扩展这种分析。首先，我们将使用新的REAP筛选 方法学，基于酵母表面展示>3000种天然构象的人类蛋白质，以鉴定 候选抗体靶标。我们将通过测试针对它们的抗体是否能 结合并抑制CIN;试点工作已经确定了三个这样的候选者，新的数据证实了CIN 被其中一个束缚。第二，通过检查来自专业治疗中心的>350名儿童的血清， 在全国范围内，我们将测试CIN结合是否特异于PANDAS或更普遍地见于PANS， 甚至是非PANS强迫症患者最后，我们将从选定的PANDAS患儿中培养单个B细胞， PANS，并将筛选他们的生产单克隆抗体对确定的目标。这将，对于 首次，使我们能够识别和克隆与这些条件相关的特异性候选自身抗体。 总之，这些创新的研究有可能从根本上推进我们对PANS的理解 和PANDAS，为基于病理生理学的疾病分类学和新的 诊断工具和治疗方法。