Differential monocyte responses to TLR ligands in children with autism spectrum disorders.
Differential monocyte responses to TLR ligands in children with autism spectrum disorders.
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DOI：
10.1016/j.bbi.2009.08.001
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发表时间：
2010-01
影响因子：
15.1
通讯作者：
Ashwood, Paul
中科院分区：
文献类型：
--
作者：
Enstrom, Amanda M.;Onore, Charity E.;de Water, Judy A. Van;Ashwood, Paul
自闭症谱系障碍(ASD)的特征是社会交往障碍、沟通障碍和受限的重复兴趣和行为。最近的证据表明，先天免疫功能受损可能在ASD中起重要作用。为了验证这一假设，我们分离了17名ASD儿童和16名年龄匹配的典型发育(TD)儿童的外周血单核细胞，并用不同的Toll样受体(TLR)配体刺激这些细胞培养：TLR2(脂磷壁酸；LTA)、TLR3(PolyI：C)、TLR4(脂多糖；LPS)、TLR5(鞭毛蛋白)和TLR9(CpG-B)。收集细胞培养上清液，用多重Luminex分析法检测IL-1、IL-6、IL-8、肿瘤坏死因子β、单核细胞趋化蛋白-1和GM-α的促炎细胞因子反应。在体外用TLR配体攻击后，ASD儿童的单核细胞培养中的细胞因子反应与TD对照组儿童不同。特别是，在自闭症儿童单核细胞培养中，IL-1β、IL-6和肿瘤坏死因子α反应在TLR2后显著增加，IL-1β反应在TLR4刺激后显著增加(p<；0.04)。相反，经TLR9刺激后，ASD患儿单核细胞培养上清液中IL-1β、IL-6、GM-CSF和肿瘤坏死因子α反应均低于对照组(P<；0.05)。这些数据表明，ASD儿童的单核细胞培养通过选择TLR对信号更敏感。由于单核细胞是免疫反应的关键调节细胞，这些细胞反应的功能障碍可能会导致ASD儿童的长期免疫变化，这可能导致不利的神经免疫相互作用的发展，并可能在ASD的病理生理观察中发挥作用。
Autism spectrum disorders (ASD) are characterized by impairment in social interactions, communication deficits, and restricted repetitive interests and behaviors. Recent evidence has suggested that impairments of innate immunity may play an important role in ASD. To test this hypothesis, we isolated peripheral blood monocytes from 17 children with ASD and 16 age-matched typically developing (TD) controls and stimulated these cell cultures in vitro with distinct toll-like receptors (TLR) ligands: TLR2 (lipoteichoic acid; LTA), TLR3 (poly I:C), TLR4 (lipopolysaccharide; LPS), TLR5 (flagellin) and TLR9 (CpG-B). Supernatants were harvested from the cell cultures and pro-inflammatory cytokine responses for IL-1β, IL-6, IL-8, TNFα, MCP-1, and GM-CSF were determined by multiplex Luminex analysis. After in vitro challenge with TLR ligands, differential cytokine responses were observed in monocyte cultures from children with ASD compared with TD control children. In particular, there was a marked increase in pro-inflammatory IL-1β, IL-6 and TNFα responses following TLR2, and IL-1β response following TLR4 stimulation in monocyte cultures from children with ASD (p<0.04). Conversely, following TLR9 stimulation there was a decrease in IL-1β, IL-6, GM-CSF and TNFα responses in monocyte cell cultures from children with ASD compared with controls (p<0.05). These data indicate that, monocyte cultures from children with ASD are more responsive to signaling via select TLRs. As monocytes are key regulators of the immune response, dysfunction in the response of these cells could result in long-term immune alterations in children with ASD that may lead to the development of adverse neuroimmune interactions and could play a role in the pathophysiology observed in ASD.
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