Anti-interneuron antibodies in abrupt-onset pediatric obsessive-compulsive disorder

突发性小儿强迫症中的抗中间神经元抗体

基本信息

批准号：
9916831
负责人：
Christopher John Pittenger
金额：
$ 18.63万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-16 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916831
关键词：
Acute Affect Antibodies Antibody Formation Antigens Autoimmune Diseases Autoimmune Process Autopsy Basal Ganglia Behavioral Binding Biological Biological Assay Brain Cells Characteristics Child Childhood Chorea Clinic Clinical Coin Consensus Corpus striatum structure DRD2 gene Data Diagnosis Diagnostic Disease Dopamine Receptor Encephalitis Etiology Event FarGo Functional disorder Future Gilles de la Tourette syndrome Goals Immune Individual Infection Inflammatory Interneurons Investigation Lead Literature Mediating Mind Molecular Target Morbidity - disease rate Mus National Institute of Mental Health Neuroimmune Neuroimmunomodulation Neuronal Dysfunction Neurons Obsessive-Compulsive Disorder Pathogenicity Pathology Patients Pattern Pediatric cohort Pilot Projects Play Population Population Heterogeneity Production Publishing Reporting Research Personnel Role Sampling Separation Anxiety Serum Severities Site Streptococcus Suggestion Sydenham Chorea Symptoms Syndrome System Testing Tic disorder Time Tissues Tubulin Universities Work Youth cellular targeting cholinergic clinical heterogeneity clinical research site cohort comorbidity cross reactivity experimental study immune function in vivo neuroinflammation neuropsychiatric disorder neuropsychiatry novel patient population phenomenological models pre-clinical preclinical study programs putamen relating to nervous system symposium symptomatic improvement symptomatology urinary

项目摘要

ABSTRACT Childhood-onset OCD is common, affecting 1-4% of youth, and causes profound morbidity. In some cases, symptom onset is remarkably rapid, even overnight. This striking presentation suggests a unique pathophysiology; the syndrome has been called ‘pediatric acute-onset neuropsychiatric disorder’, or PANS. Onset is often temporally associated with inflammatory illness, suggesting a neuroimmune mechanism, and immune-modulating treatments are sometimes used. However, pathophysiological details have been difficult to pin down, and the diagnostic landscape remains unclear. One specific etiopathophysiological hypothesis is that infectious illness can, in a susceptible host, lead to the production of antibodies cross-reactive with brain antigens. Consequent brain inflammation is proposed to produce neural dysfunction and clinical phenomenology; an analogy is sometimes drawn to Sydenham’s chorea, in which a similar antibody-mediated pathophysiology has been more clearly demonstrated. This proposal implies that there should be pathogenic antibodies in patients that are not found in controls. A number of studies have sought to characterize such antibodies, and reports have been published of antibodies reactive with D1R and D2R dopamine receptors, tubulin, and other antigens; but non-replication is common in this literature, and it remains unclear what antibodies, if any, contribute to disease. Identification of antibodies clearly associated with symptom onset or severity in PANS, or in any subset of PANS patients, would go far to clarify pathophysiology and diagnostic complexity in this population. With this goal in mind, we investigated antibody binding using a novel in vivo assay in mice. Rather than focusing on specific molecular targets, as most previous studies have done, we sought to examine cellular targets of illness-associated antibodies; and we did so in intact tissue, rather than in reduced systems. In recently published work we described elevated binding to cholinergic interneurons (CINs) in the striatum by antibodies from patients with pediatric autoimmune disorder associated with Streptococcus, or PANDAS, a narrower diagnosis related to PANS.9 CINS have previously been implicated in the pathophysiology of tic disorders and OCD, in post-mortem and preclinical work from our group and others. The suggestion that antibody binding to these interneurons may contribute to pathophysiology thus has immediate plausibility and merits further investigation. In unpublished pilot data we have reproduced this finding using a more efficient ex vivo assay and replicated it in a second small cohort of PANDAS patients. We now propose to replicate, refine, or refute the provocative finding from these pilot data by examining a larger cohort of patients. We will continue to focus on patients with PANDAS in order to limit clinical heterogeneity, but we will examine patients from three different clinical cohorts across two sites (NIMH and the Stanford PANS Clinic) to clarify the generalizability of the findings from our pilot studies. We will examine a total of N = 38 patients and 38 matched controls; when combined with our pilot studies, we will have a total of N = 49 PANDAS patients, which allow well-powered examination of correlation of CIN binding with symptom severity and other clinical variables. If our pilot findings are upheld, this will set the stage for future experiments examining more heterogeneous clinical samples.

抽象的儿童期强迫症很常见，影响1-4％的年轻人，并引起严重的发病率。在某些情况下，症状发作非常迅速，甚至一夜之间。这种引人注目的表现提出了独特的病理生理学。综合征被称为“小儿急性发作的神经精神疾病”或PANS。发作通常与有时会使用炎性疾病，表明神经免疫机制和免疫调节治疗。但是，病理生理细节很难固定，并且诊断景观尚不清楚。一种特定的病态生理学假设是，在易感宿主中，感染性疾病可以导致与脑抗原交叉反应的抗体产生。因此，提出大脑感染可产生中性功能障碍和临床现象学；有时比喻与Sydenham的唱片相似，其中类似抗体介导的病理生理学已被更清楚地证明。该提议意味着应该有对照组未发现的患者的致病抗体。许多研究已经表征了这样的表征抗体和报告已经发表了与D1R和D2R多巴胺受体反应性的抗体，微管蛋白和其他抗原；但是在本文献中，非复制是常见的，目前尚不清楚哪些抗体（如果有）有助于哪些抗体疾病。鉴定与pan的症状发作或严重程度相关的抗体，或在任何子集中 PANS患者将阐明该人群的病理生理学和诊断复杂性。考虑到这一目标，我们使用小鼠中新型的体内测定法研究了抗体结合。而不是专注于与以前的大多数研究一样，特定的分子靶标，我们试图检查与疾病相关的细胞靶标抗体；我们在完整的组织中而不是在减少的系统中这样做。在最近发表的工作中，我们描述了小儿自身免疫性患者的抗体与纹状体中胆碱能中间神经元（CIN）的结合升高与链球菌或熊猫相关的疾病，与PANS相关的较窄诊断。9CINS以前是在TIC疾病和强迫症的病理生理学中，在我们小组的验尸和临床前工作中实施其他的。因此，与这些中间神经元结合的抗体结合可能有助于病理生理学的建议立即合理并值得进一步调查。在未发表的飞行员数据中，我们使用更有效的离体测定法，并在第二个小型熊猫患者队列中进行了复制。现在，我们建议通过检查较大的数据来复制，完善或反驳这些试验数据的挑衅性发现患者队列。我们将继续专注于熊猫患者，以限制临床异质性，但我们将检查来自两个部位（NIMH和Stanford Pans诊所）的三个不同临床队列的患者，以澄清我们的试点研究的发现的概括性。我们将检查总共n = 38名患者和38例匹配对照。当与我们的试验研究结合使用时，我们将总共有n = 49例熊猫患者检查CIN结合与症状严重程度和其他临床变量的相关性。如果我们的飞行员发现是坚持认为，这将为未来检查更多异质临床样本的实验奠定基础。