孤獨症也是免疫性疾病？

來自四川大學的一項跨界的研究，解開孤獨症的免疫調控異常的謎團。

撰文 許文明 （論文通訊作者，四川大學華西第二醫院研究員）

編輯 譚坤

近年來，越來越多的研究表明神經、精神類疾病如精神分裂症、阿茲海默症的發生與免疫系統的異常有關。孤獨症是一類以刻板動作，社交障礙為核心癥狀的兒童神經發育性疾病，然而，在兒童孤獨症患者中是否有哪些免疫系統的異常，並無系統性的研究。近日來自於四川大學華西第二醫院許文明教授課題組與西南交通大學臨床醫院謝江教授的一項合作研究，針對孤獨症兒童的免疫特性及與孤獨症兒童的行為異常的關係進行了系統的研究，為這一問題提供了新的見解。

在該項研究中，該研究小組採集了西南地區的孤獨症 (ASD) 以及年齡，性別相似的30例健康對照兒童的外周血。在檢測血常規與其他血液學參數基礎上，用 MILLIPLEX 多因子檢測試劑盒檢測了與 Th1,Th2,及Th-17 細胞功能相關的11種細胞因子，同時測定自閉症行為量表（ABC）和 M-CHAT 量表。在此基礎上，對已知差異表達最顯著的 TNF-a 的調節長非編碼 RNA,LincR-1992 的表達水平通過定量PCR進行了驗證。結果顯示在檢測的11個與先天免疫及 Th-17細胞相關的細胞因子中，ASD 兒童的 TNF-alpha 有顯著升高（P

在本研究中發現的 TNF-alpha 是腫瘤與免疫性疾病治療的重要靶點。由於這一類因子母親已有相應的抗體藥物（目前全球最暢銷的針對免疫性疾病藥物的靶點即為TNF-alpha），針對患者的免疫系統異常，特別是 TNF-alpha 相關調節通路的藥物干預可能是對免疫異常相關的自閉症兒童干預的非常有前景的方法。

這一研究同時也為進一步了解免疫功能的失常與孤獨症的關係提出了新的研究方向，例如，是否在新生兒的免疫系統即會出現 TNF 的分泌異常；在早期先天免疫的建立在母胎界面的維持中起關鍵作用，在孤獨症兒童孕期的哪個階段是導致這一信號通路的改變；這些改變能否在早期通過藥物逆轉，對這些問題的探討將為孤獨症兒童的發病機理的探討與早期干預提供新的思路。

這一研究發表在最近發表的國際生物醫學雜誌oncotarget。

四川大學華西第二醫院許文明教授與西南交通大學臨床醫院（成都市第三人民醫院）謝江教授的合作團隊部分成員合影

相關論文信息

標題Immunological cytokine profiling identifies TNF-α as a key molecule dysregulated in autistic children

期刊Oncotarget

doi:10.18632/oncotarget.19326.

作者Jiang Xie, Li Huang, Xiaohong Li, Hua Li, Yongmei Zhou, Hua Zhu, Tianying Pan, Keith M. Kendrick and Wenming Xu

發表時間Accepted: June 11, 2017 Published: July 18, 2017

摘要Recent studies have suggested that the etiology of Autism Spectrum Disorder (ASD) may be caused by immunological factors, particularly abnormalities in the innate immune system. However, it is still unclear which specific cytokines may be of most importance. The current study therefore investigated which cytokines showed altered concentrations in blood in ASD compared with healthy control children and which were also correlated with symptom severity. Our study sample included 32 children diagnosed with ASD and 28 age and sex-matched typically developing children. Autism symptoms were measured using the Autistic Behavior Checklist (ABC) and blood samples were taken from all subjects. We used Milliplex cytokine kits to determine serum concentrations of 11 Th1, Th2 and Th17 related cytokines. Additionally, expression of THRIL (TNFα and hnRNPL related immunoregulatory LincRNA), a long non-coding RNA involved in the regulation of tumor necrosis factor- α (TNF-α), was determined using real–time PCR. Of the 11 cytokines measured only concentrations of TNF-α (p=0.002), IL-1β (p=0.02) and IL-17a (p=0.049) were significantly increased in ASD children compared to typically developing controls, but only TNF-α concentrations were positively correlated with severity of ASD symptoms on all 5 different ABC sub-scales and were predictive of an ASD phenotype (area under the curve = 0.74). Furthermore, THRIL RNA expression was significantly decreased in ASD children. Our results provide further support for altered innate immunity being an important autism pathogenic factor, with autistic children showing increased blood TNF-α concentrations associated with symptom severity, and decreased expression of the THRIL gene involved in regulating TNF-α.

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