Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症谱系障碍 (ASD) 的神经免疫学研究

• 批准号: 8745745
• 负责人: Susan Swedo
• 金额: $ 16.29万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8745745
• 关键词: Age; American; Antibodies; Astrocytes; Autistic Disorder; Autopsy; Behavior; Behavioral; Biological Assay; Borrelia burgdorferi; Brain; Cerebrospinal Fluid; Child; Chronic; Data; Development; Developmental Delay Disorders; Environmental Risk Factor; Etiology; Family; Functional disorder; Genetic; Immune System Diseases; Immune system; Immunologic Markers; Individual; Inflammation; Inflammatory; Injury; Intervention; Intestines; Investigation; Life; Literature; Lyme Disease; MRI Scans; Maternal antibody; Microglia; Minocycline; Mothers; NF-kappa B; Nature; Neurotoxins; Nuclear Translocation; Paper; Pathologic; Pattern; Pharmacologic Substance; Phenotype; Play; Prevalence; Public Health; Recording of previous events; Reporting; Research; Research Priority; Role; Sampling; Scanning; Serum; Symptoms; Time; Universities; autism spectrum disorder; autistic children; chemokine; cohort; cytokine; effective therapy; immune function; interest; microbial; neuroinflammation; neurotoxic; novel therapeutic intervention; open label; prevent; response; sample collection; skills; social communication; suspected autism; therapeutic target; transcription factor

Autism is defined by its behavioral manifestations: social-communication deficits and the presence of restricted or repetitive behaviors. The cause of these abnormalities is unknown, but it is strongly suspected that autism spectrum disorders (ASD) result from a combination of genetic and environmental factors. The rising prevalence rates of ASD and the life-long, often debilitating nature of the symptoms combine to make autism spectrum disorders a major public health problem. Research that increases our understanding of the causes and nature of the symptoms, and studies that investigate the potential role for novel therapeutic interventions hold the promise of benefit for millions of American families. A growing literature supports a role for neuroimmune dysfunction in autism spectrum disorders (ASD), including observations of abnormal patterns of CSF cytokines and chemokines, and pathological reports of chronic neuroinflammatory changes among individuals with ASD. Evidence thus far supports that neuroimmune dysfunction may play prominent role in certain cases of autism, including those with a history of significant regression. If this hypothesis is correct, we would expect to find that at least some autistic children, particularly those with a history of regression, will have demonstrable abnormalities in immune function. Thus, we are continuing to collect data on a cohort of young children with autism that have been well-characterized and studied longitudinally. We are exploring immune markers in the CNS as well as peripherally. Finding new and effective treatments for autism is one of PDN's highest research priorities. One potential target was provided by a paper from Johns Hopkins University (D. Vargas et al, 2005) reporting that autopsy material from individuals with autism showed evidence of chronic brain neuroinflammation, as exemplified by activation of microglia and astroglia. The authors remarked that chronic microglia activation appeared to be responsible for a sustained neuroinflammatory response which could be producing neurotoxic factors. (Alternatively, neuroglial activation could occur in response to the presence of neurotoxins and thus represent the result, rather than the cause, of the injury.) The neuroinflammatory changes associated with neuroglial activation can be prevented by blocking nuclear translocation of the pro-inflammatory transcription factor NF-kappaB. Having completed an open-label trial of minocycline, an agent shown to inhibit NF KappaB, wherein neither immune markers (e.g. CSF and serum cyotkines and chemokines) nor behavioral status changed, we continue to explore targets for further pharmaceutical intervention. The phenotyping study (NCT 00298246) is also continuing efforts to identify individuals with evidence of ongoing neuroinflammation as a potential cohort for targeted therapeutic efforts. Markers under investigation include those that relate to direct evidence of immune dysfunction in relation to core symptoms of autism, as well as in relation to associated features, such as gastro-intestinal problems in a subset of children. Previously collected samples have also been used to demonstrate that, contrary to a highly publicized report, children with autism do not have circulating antibodies against Borrelia burgdorferi (as would be seen in Lyme Disease); nor was there any evidence of microbial translocation, which had been proposed as an etiologic factor in autism (the so-called "leaky gut" hypothesis). In both studies, there were no discernable differences between samples obtained from typically developing children and those from children with autism. More recently, serum samples have been obtained from mothers of children with autism or typical development in order to evaluate recent reports that maternal antibodies play a role in the etiology of autism. The antibody assays, and others, will commence when sample collection is completed over the next few months.

自闭症是由其行为表现来定义的：社交沟通缺陷和存在限制或重复行为。 这些异常的原因尚不清楚，但强烈怀疑自闭症谱系障碍（ASD）是遗传和环境因素共同作用的结果。 自闭症谱系障碍患病率的上升和症状的终身性，通常使人衰弱的性质联合收割机结合在一起，使自闭症谱系障碍成为一个主要的公共卫生问题。 增加我们对症状的原因和性质的理解的研究，以及调查新的治疗干预措施的潜在作用的研究，有望使数百万美国家庭受益。 越来越多的文献支持神经免疫功能障碍在自闭症谱系障碍（ASD）中的作用，包括CSF细胞因子和趋化因子异常模式的观察，以及ASD患者慢性神经炎症变化的病理报告。 迄今为止的证据支持神经免疫功能障碍可能在某些自闭症病例中起着重要作用，包括那些有显著退化史的病例。 如果这一假设是正确的，我们将发现至少有一些自闭症儿童，特别是那些有退化史的儿童，会有明显的免疫功能异常。 因此，我们正在继续收集一组自闭症幼儿的数据，这些数据已经得到了很好的描述和纵向研究。我们正在探索中枢神经系统以及外周的免疫标志物。 寻找新的有效的自闭症治疗方法是PDN的最高研究优先事项之一。约翰霍普金斯大学的一篇论文（D. Vargas等人，2005年）报告说，自闭症患者的尸检材料显示慢性脑神经炎症的证据，如小胶质细胞和星形胶质细胞的活化所示。 作者指出，慢性小胶质细胞活化似乎是持续神经炎症反应的原因，这可能会产生神经毒性因子。 （或者，神经胶质细胞的激活可能是对神经毒素存在的反应，因此代表了损伤的结果，而不是原因。 与神经胶质细胞活化相关的神经炎症变化可以通过阻断促炎转录因子NF-κ B的核转位来预防。 在完成米诺环素的开放标签试验后，我们继续探索进一步药物干预的靶点，米诺环素是一种抑制NF KappaB的药物，其中免疫标志物（例如CSF和血清细胞因子和趋化因子）和行为状态均未改变。 表型研究（NCT 00298246）也在继续努力，以确定具有持续神经炎症证据的个体作为靶向治疗工作的潜在队列。 正在调查的标志物包括那些与自闭症核心症状相关的免疫功能障碍的直接证据有关的标志物，以及与相关特征相关的标志物，例如儿童亚群的胃肠道问题。 以前收集的样本也被用来证明，与一个高度宣传的报告相反，自闭症儿童没有针对伯氏疏螺旋体的循环抗体（如莱姆病中所见）;也没有任何微生物易位的证据，这被认为是自闭症的病因因素（所谓的“漏肠”假说）。 在这两项研究中，从发育正常的儿童和自闭症儿童中获得的样本之间没有明显的差异。 最近，已从患有自闭症或典型发育的儿童的母亲获得血清样品，以评估最近关于母体抗体在自闭症病因学中发挥作用的报道。 抗体检测和其他检测将在未来几个月内完成样本采集后开始。