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.

抽象的儿童期发病的强迫症很常见，影响 1-4% 的青少年，在某些情况下会导致严重的发病症状。发病速度异常迅速，甚至在一夜之间就可发生。被称为“小儿急性发作性神经精神障碍”，或 PANS，发病通常与时间相关。炎症性疾病，表明存在神经免疫机制，有时会使用免疫调节治疗。然而，病理生理学细节很难确定，诊断情况仍不清楚。一个具体的病因病理生理学假设是，传染病可以在易感宿主中导致产生与脑抗原交叉反应的抗体，从而产生神经炎症。功能障碍和临床现象学有时会与西德纳姆舞蹈病进行类比，其中有类似的情况抗体介导的病理生理学已得到更清楚的证明，这一提议意味着应该存在。许多研究试图表征患者体内未发现的致病性抗体。抗体，并且已经发表了与 D1R 和 D2R 多巴胺受体、微管蛋白和其他抗原；但非复制在该文献中很常见，并且尚不清楚哪些抗体（如果有）起作用鉴定与 PANS 或任何亚型症状出现或严重程度明显相关的抗体。 PANS 患者的病理生理学和诊断复杂性将得到进一步阐明。考虑到这一目标，我们使用一种新型的小鼠体内抗体结合研究，而不是专注于测定。正如大多数先前的研究所做的那样，我们试图检查与疾病相关的细胞靶标抗体；并且我们是在完整的组织中进行的，而不是在我们最近发表的工作中描述的。来自儿科自身免疫性疾病患者的抗体与纹状体中胆碱能中间神经元（CIN）的结合增加与链球菌相关的疾病 (PANDAS)，这是一种与 PANS 相关的狭义诊断。9 CINS 之前已被与抽动障碍和强迫症的病理生理学有关，在我们小组的尸检和临床前工作中，因此，有人认为抗体与这些中间神经元的结合可能有助于病理生理学。在未发表的试点数据中，我们使用了这一发现。一种更有效的离体检测方法，并在第二组 PANDAS 患者中进行了复制。我们现在建议通过检查更大范围的数据来复制、完善或反驳这些试点数据中的挑衅性发现。我们将继续关注 PANDAS 患者，以限制临床异质性，但我们会检查来自两个地点（NIMH 和斯坦福 PANS 诊所）的三个不同临床队列的患者，以澄清我们将检查总共 N = 38 名患者和 38 名匹配的对照组；与我们的试点研究相结合，我们总共将有 N = 49 名 PANDAS 患者，这使得他们能够检查 CIN 与症状严重程度和其他临床变量的相关性。如果得到证实，这将为未来检查更多异质临床样本的实验奠定基础。