Autism genes and the leukocyte transcriptome in autistic toddlers relate to pathogen interactomes, infection and the immune system. A role for excess neurotrophic sAPPα and reduced antimicrobial Aβ
Autism genes and the leukocyte transcriptome in autistic toddlers relate to pathogen interactomes, infection and the immune system. A role for excess neurotrophic sAPPα and reduced antimicrobial Aβ
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DOI：
10.1016/j.neuint.2019.03.007
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发表时间：
2019-06-01
影响因子：
4.2
通讯作者：
Carter, C. J.
中科院分区：
文献类型：
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作者：
Carter, C. J.
产前和儿童早期感染与自闭症有关。许多自闭症易感基因（206个Autworks基因）位于免疫系统中，与免疫/感染途径有关。它们富含18种不同微生物（细菌/病毒和真菌）的宿主/病原体相互作用组以及细菌毒素、真菌毒素和Toll样受体配体调节的基因。从自闭症幼儿白细胞的微阵列研究中也观察到了这种富集的失调基因。来自该白细胞研究的上调基因也与来自布罗德研究所分子特征数据库的响应于许多感染因子的表达谱相匹配。他们还匹配了与婴儿猝死综合症和自闭症共病有关的基因（自身免疫性疾病、系统性红斑狼疮、糖尿病、癫痫和心肌病）以及雌激素和促甲状腺激素反应和由不同类型的应激源（包括氧化应激、缺氧、内质网应激、紫外线辐射或2，4-二硝基氟苯）上调的那些，一种用于在动物模型中产生过敏性皮肤反应的半抗原。氧化/整合应激反应也在自闭症大脑中上调，并可能导致髓鞘形成问题。自闭症和阿尔茨海默病的表达特征之间也有明显的相似性，44个共有的自闭症/阿尔茨海默病基因几乎只在血脑屏障中表达。然而，与阿尔茨海默病相反，自闭症患者的抗微生物肽β-淀粉样蛋白水平降低，神经营养/髓鞘营养可溶性APP α水平升高，α-分泌酶活性升高。sAPP α诱导产生兴奋性/抑制性失衡的GABA能突触的增加和GABA能突触的减少，这也在自闭症中观察到。一项文献调查显示，多种自闭症基因聚集在APP处理上，许多基因能够以β淀粉样蛋白的产生为代价增加sAPP α。该轴向神经营养/神经胶质营养sAPP α的过度产生和抗微生物β-淀粉样蛋白的生产不足的遗传程序化倾斜可以解释大脑过度生长和髓鞘形成功能障碍，以及自闭症中病原体的参与。
Prenatal and early childhood infections have been implicated in autism. Many autism susceptibility genes (206 Autworks genes) are localised in the immune system and are related to immune/infection pathways. They are enriched in the host/pathogen interactomes of 18 separate microbes (bacteria/viruses and fungi) and to the genes regulated by bacterial toxins, mycotoxins and Toll-like receptor ligands. This enrichment was also observed for misregulated genes from a microarray study of leukocytes from autistic toddlers. The upregulated genes from this leukocyte study also matched the expression profiles in response to numerous infectious agents from the Broad Institute molecular signatures database. They also matched genes related to sudden infant death syndrome and autism comorbid conditions (autoimmune disease, systemic lupus erythematosus, diabetes, epilepsy and cardiomyopathy) as well as to estrogen and thyrotropin responses and to those upregulated by different types of stressors including oxidative stress, hypoxia, endoplasmic reticulum stress, ultraviolet radiation or 2,4-dinitrofluorobenzene, a hapten used to develop allergic skin reactions in animal models. The oxidative/integrated stress response is also upregulated in the autism brain and may contribute to myelination problems. There was also a marked similarity between the expression signatures of autism and Alzheimer's disease, and 44 shared autism/Alzheimer's disease genes are almost exclusively expressed in the blood-brain barrier. However, in contrast to Alzheimer's disease, levels of the antimicrobial peptide beta-amyloid are decreased and the levels of the neurotrophic/myelinotrophic soluble APP alpha are increased in autism, together with an increased activity of a-secretase. sAPP alpha induces an increase in glutamatergic and a decrease in GABA-ergic synapses creating and excitatory/inhibitory imbalance that has also been observed in autism. A literature survey showed that multiple autism genes converge on APP processing and that many are able to increase sAPPalpha at the expense of beta-amyloid production. A genetically programmed tilt of this axis towards an overproduction of neurotrophic/gliotrophic sAPPalpha and underproduction of antimicrobial beta-amyloid may explain the brain overgrowth and myelination dysfunction, as well as the involvement of pathogens in autism.