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

• 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
• 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

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.

摘要 儿童期发病的强迫症是常见的，影响1-4%的青年，并导致严重的发病率。在某些情况下，症状 发病速度非常快，甚至在一夜之间。这种引人注目的表现表明了一种独特的病理生理学; 被称为“小儿急性发作性神经精神障碍”，简称PANS。发病时间通常与 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，病理生理学的细节一直难以确定，诊断前景仍然不清楚。 一个特定的病因病理生理学假设是，在易感宿主中，感染性疾病可导致 产生与脑抗原交叉反应的抗体。连续性脑炎症被认为是产生神经 功能障碍和临床现象学;一个类比是有时提请西德纳姆的舞蹈病，其中类似的 抗体介导的病理生理学已经被更清楚地证明。这一建议意味着， 在对照组中未发现的病原抗体。一些研究试图描述这种 抗体，并且已经公开了与D1 R和D2 R多巴胺受体、微管蛋白和 其他抗原;但非复制在这篇文献中很常见，目前仍不清楚是什么抗体，如果有的话， 疾病。在PANS或任何子集中，确定与症状发作或严重程度明确相关的抗体 PANS患者，将远远澄清病理生理学和诊断的复杂性，在这个群体。 考虑到这一目标，我们使用一种新的小鼠体内试验研究了抗体结合。而不是专注于 正如大多数以前的研究所做的那样，我们试图检查疾病相关的细胞靶点， 我们在完整的组织中这样做，而不是在减少的系统中。在最近发表的研究中， 来自儿童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）的结合升高 与链球菌相关的疾病，或PANDAS，与PANS相关的狭义诊断。 涉及抽动障碍和强迫症的病理生理学，我们小组的尸检和临床前工作， 他人因此，与这些中间神经元结合的抗体可能有助于病理生理学的建议， 立即可行，值得进一步调查。在未发表的试验数据中，我们使用 一个更有效的离体试验，并复制它在第二个小组的PANDAS患者。 我们现在建议通过检查一个更大的 患者队列。我们将继续关注PANDAS患者，以限制临床异质性，但我们将 检查来自两个研究中心（NIMH和斯坦福大学PANS诊所）的三个不同临床队列的患者，以阐明 我们的试点研究结果的普遍性。我们将检查总共N = 38名患者和38名匹配的对照; 当与我们的初步研究相结合时，我们将总共有N = 49例PANDAS患者，这使得有充分的把握度。 检查CIN结合与症状严重程度和其他临床变量的相关性。如果我们的试点发现 支持，这将为未来的实验研究更多的异质性临床样本奠定基础。