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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的强迫症会影响1-4％的儿童，并产生大量的发病率和破坏正常发展。在某些孩子中，快速发作和一组参与的符号提出独特的病理生理学；这被称为“小儿急性发作的神经精神综合症”，或锅。 Pans发作通常是在感染性疾病后发生的小儿强迫症是由神经炎症过程触发的。具体而言，已经提出确定在易感儿童中，感染可以导致产生与大脑反应的自身抗体表位并导致基底神经节感染，从而导致OCD症状。这些目标自身抗体尚不清楚，自身免疫的假设是引起锅的原因。在最近的工作中，我们使用一种新颖的方法来表征熊猫儿童的抗体结合（与链球菌相关的小儿自身免疫性神经精神疾病），一种锅的形式症状暂时与链球菌感染与脑组织有关。我们发现了，乘以复制的是，来自熊猫儿童的IgG与尾状的特定中间神经元结合鬼盘：胆碱能中间神经元或CINS。通过熊猫相关的IgG结合CIN降低了其活性在两个离体测定中。两种效果 - IgG与CIN的结合和活动的减少 - 在儿童中丢失在免疫调节疗法后暴露了症状改善。 CIN病理学一直是与图雷特综合症独立相关，我们发现CIN中断导致重复小鼠的行为病理。这些收敛的发现为新的假设提供了固有的合理性与CIN的抗体结合并因此抑制了熊猫的病理生理。在这里，我们以关键的方式测试和扩展此分析。首先，我们将使用新颖的收获筛选基于酵母表面在其天然构象中> 3000人蛋白的表面显示，以识别候选抗体靶标。我们将通过测试针对它们的抗体是否可以验证这些候选者结合并抑制CINS；飞行员工作已经确定了三个这样的候选人，新数据证实了CIN 由其中一个约束。第二，通过检查> 350名从专业治疗中心吸引的儿童的血清在全国范围内，我们将测试CIN绑定是特定于Pandas还是在Pans中更普遍地看到甚至在非潘帝国强迫症中。最后，我们将培养来自选定儿童患有熊猫的儿童的单个B细胞，平底锅并将筛选它们以生产针对已识别靶标的单克隆抗体。这将是第一次，允许我们识别和克隆特定的候选自身抗体与这些条件相关的自身抗体。这些创新的研究共同有潜力从根本上提高我们对平底锅的理解和大熊猫，为基于病理生理学的疾病学和新的发展铺平了道路诊断工具和治疗。