Neuroimmunologic Investigations of Autism Spectrum Disorders (ASD)

自闭症是通过其行为表现来定义的：社交缺陷、交流障碍以及存在受限或重复的行为。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。自闭症患病率不断上升(最近一次报道，影响到每100名儿童中就有1人受到影响)，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。神经免疫功能障碍被认为是退行性自闭症的潜在病因，据报道，自闭症儿童有一段时间的正常发育，然后开始失去社交和沟通技能。退行性自闭症(尤其是急性或半急性自闭症)的临床病程与影响中枢神经系统的免疫功能变化是一致的。如果这一假设是正确的，我们预计会发现至少一些有退化史的自闭症儿童会有明显的免疫功能异常。这些异常预计不会在没有倒退病程的自闭症儿童中发现，也不应该出现在典型发育中儿童或非自闭症发育迟缓儿童的对照组中。 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。米诺环素已被证明可以抑制核因子-kappaB的产生，并已用于一些神经炎性疾病，疗效不大。我们进行了一项米诺环素的开放标签试验，以确定该药物是否对自闭症行为或改变脑脊液或血清细胞因子或趋化因子的分布模式有影响。米诺环素在儿童的发育轨迹或整体行为方面没有明显的改善；它也没有显著改变脑脊液或血清中细胞因子或趋化因子的模式。因此，没有计划对米诺环素进行进一步的研究，但在其他PDN项目中继续寻找新的治疗剂。表型研究还在继续努力识别有持续神经炎证据的个体，作为靶向治疗努力的潜在队列。

Autism is defined by its behavioral manifestations: social deficits, impairments in communication 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 (last reported to affect as many as 1 in 100 children) 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. Neuroimmune dysfunction is considered to be a potential etiologic factor in regressive autism where children are reported to have had a period of normal development and then began losing social and communication skills. The clinical course of regressive autism (particularly when it occurs acutely or semi-acutely) is consistent with alterations in immune function that are impacting on the central nervous system. If this hypothesis is correct, we would expect to find that at least some autistic children with a history of regression will have demonstrable abnormalities in immune function. These abnormalities are not expected to be found among autistic children without a regressive course; nor should they be present in the contrast groups of typically developing children or children with non-autistic developmental delays. 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. Minocycline has been shown to inhibit NF-kappaB production and has been used with modest benefit in a number of neuroinflammatory disorders. We undertook an open-label trial of minocycline to determine if the drug might have an effect on autistic behaviors or change patterns of distribution for the CSF or serum cytokines or chemokines. Minocycline produced no discernable improvements in the children's developmental trajectory or overall behavior; it also failed to significantly change the patterns of cytokines or chemokines in CSF or serum. Thus, no further investigations are planned for minocycline, but the search for novel therapeutic agents continues in other PDN projects. The phenotyping study is also continuing efforts to identify individuals with evidence of ongoing neuroinflammation as a potential cohort for targeted therapeutic efforts.