Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症是通过其行为表现来定义的：社交沟通障碍和限制性或重复性行为的存在。这些异常的原因尚不清楚，但人们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。自闭症患病率的上升，以及这些症状的终生、往往令人虚弱的性质，共同使自闭症谱系障碍成为一个主要的公共卫生问题。增加我们对症状原因和本质的理解的研究，以及调查新的治疗干预措施的潜在作用的研究，有望为数百万美国家庭带来好处。 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，包括观察脑脊液细胞因子和趋化因子的异常模式，以及ASD患者慢性神经炎性改变的病理报告。到目前为止，有证据表明，神经免疫功能障碍可能在某些自闭症病例中发挥重要作用，包括那些有显著退化史的病例。如果这一假设是正确的，我们预计会发现至少一些自闭症儿童，特别是那些有退化史的儿童，将会有明显的免疫功能异常。因此，我们正在继续收集一组患有自闭症的儿童的数据，这些儿童已经被很好地描述了特征并进行了纵向研究。我们正在探索中枢神经系统以及外围的免疫标记物。 寻找新的有效的自闭症治疗方法是PDN的最高研究重点之一。约翰霍普金斯大学(D.Vargas等人，2005年)的一篇论文提供了一个潜在的靶点，报告称来自自闭症患者的尸检材料显示有慢性脑神经炎症的证据，例如小胶质细胞和星形胶质细胞的激活。作者评论说，慢性小胶质细胞的激活似乎与持续的神经炎性反应有关，后者可能产生神经毒性因子。(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。)与神经胶质细胞激活相关的神经炎性改变可以通过阻断促炎转录因子NF-kappaB的核转位来预防。在完成了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。米诺环素是一种被证明抑制核因子kappaB的药物，其中免疫标记物(例如，脑脊液和血清细胞因子和趋化因子)和行为状态都没有改变。 表型研究(议定书06-M-0102，NCT 00298246)也在继续努力，以确定有持续神经炎证据的个体作为靶向治疗努力的潜在队列。正在调查的标记物包括与自闭症核心症状有关的免疫功能障碍的直接证据，以及与相关特征有关的标记物，如部分儿童的胃肠道问题。以前收集的样本也被用来证明，与一份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(在莱姆病中会看到)；也没有任何证据表明微生物易位，这被认为是自闭症的病因(所谓的“肠道渗漏”假说)。在这两项研究中，从发育正常的儿童和自闭症儿童获得的样本之间没有明显的差异。最近，从患有自闭症或典型发育的儿童的母亲那里获得了血清样本，以评估最近关于母体抗体在自闭症病因中发挥作用的报道。自闭症儿童的样本也正在接受各种自身反应抗体的检测。

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 cytokines and chemokines) nor behavioral status changed, we continue to explore targets for further pharmaceutical intervention. The phenotyping study (Protocol 06-M-0102, 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. Samples of children with autism are also being tested for a variety of autoreactive antibodies.