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 儿童期起病的强迫症很常见，影响到1-4%的年轻人，并导致严重的发病率。在某些情况下，症状 发病非常迅速，即使是一夜之间也是如此。这一引人注目的表现表明了一种独特的病理生理学；综合征 已被称为“儿科急性起病神经精神障碍”，简称PANS。发病通常在时间上与 炎症性疾病，暗示了神经免疫机制，有时也会使用免疫调节治疗。 然而，病理生理细节很难确定，诊断前景仍然不清楚。 一种特定的病因生理学假说是，在易感宿主中，感染性疾病可导致 产生与大脑抗原交叉反应的抗体。随之而来的脑部炎症被认为是产生神经 功能障碍和临床现象学；有时会被比作赛德纳姆舞蹈症，在那里类似的 抗体介导的病理生理学已经得到了更清楚的证明。这项建议暗示，应该有 在对照组中未发现的患者中的致病抗体。许多研究试图对这种情况进行描述 抗体，以及与D1R和D2R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，如果有抗体的话，还不清楚是什么抗体起作用。 为了疾病。在PAN中或在PAN的任何子集中识别与症状出现或严重程度明显相关的抗体 PANS患者，将进一步阐明这一人群的病理生理学和诊断复杂性。 考虑到这一目标，我们使用一种新的小鼠体内试验来研究抗体结合。与其把重点放在 特定的分子靶点，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。 抗体；我们在完整的组织中做到了这一点，而不是在减少的系统中。在最近出版的著作中，我们描述了 儿童自身免疫性疾病患者抗体与纹状体内胆碱能中间神经元的结合 与链球菌或熊猫相关的疾病，与PANS.9相关的狭义诊断 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 其他。因此，与这些中间神经元结合的抗体可能有助于病理生理的提示 直接可信，值得进一步调查。在未发表的试验数据中，我们使用以下方法复制了这一发现 一种更有效的体外试验，并在另一小群熊猫患者身上复制了这一方法。 我们现在建议复制、改进或驳斥来自这些试点数据的挑衅性发现，方法是研究更大的 一群病人。我们将继续关注熊猫患者，以限制临床异质性，但我们将 检查来自两个地点(NIMH和斯坦福潘斯诊所)的三个不同临床队列的患者，以澄清 对我们的初步研究结果的概括性。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名熊猫患者，这使得 CIN结合与症状严重程度等临床变量的相关性检验。如果我们的试验结果是 如果得到支持，这将为未来检测更多异质临床样本的实验奠定基础。