神经免疫指标与孤独症谱系障碍的关联
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摘要
目的探讨骨桥蛋白(osteopontin, OPN)、白介素17A(interleukin-17A, IL-17A)、抗髓鞘碱性蛋白抗体(anti-MBP auto-antibody)与孤独症谱系障碍(autism spectrum disorder, ASD)的关系,为ASD的病因及发病机制研究提供理论依据。方法采用病例对照研究方法,收集哈尔滨市孤独症康复定点机构进行康复训练的ASD儿童40例作为病例组,1∶1性别、年龄匹配的正常儿童作为对照组。应用酶联免疫吸附试验(ELISA)方法检测两组儿童血清OPN,IL-17A,anti-MBP auto-antibody水平,并采用Pearson或Spearman相关与ASD儿童严重程度及智力水平进行关联分析。结果 ASD组血清OPN,IL-17A水平[(296.89±162.95),0.93]pg/mL均高于对照组[(217.98±113.39),0.62]pg/mL(P值均<0.05)。ASD组血清OPN,IL-17A,anti-MBP auto-antibody水平与儿童孤独症行为量表(ABC),儿童孤独症评定量表(CARS),皮博迪图片词汇测验(PPVT)得分相关均无统计学意义(P值均>0.05),ASD组血清anti-MBP auto-antibody与OPN,IL-17A均呈正相关(r值分别为0.35,0.34,P值均<0.05)。结论 ASD儿童存在明显的神经免疫异常,机制有待进一步探讨。
Objective To explore the relationship among osteopontin(OPN), Interleukin-17 A(IL-17 A), anti-MBP auto-antibody and autism spectrum disorder(ASD), and to provide the theoretical basis for the etiology and pathogenesis of ASD. Methods Forty autistic children and forty matched healthy children were enrolled in this case-control study. The levels of OPN, IL-17 A, anti-MBP auto-antibody in serum were measured by enzyme-linked immunosorbent assay(ELISA). The associations between those metabolic levels and the severity and intelligence of ASD children were performed by Pearson or Spearman correlation. Results Children with ASD had higher serum levels of OPN, IL-17 A [(296.89±162.95),0.93] pg/mL compared to healthy control[(217.98±113.39), 0.62] pg/mL(P<0.05). Serum OPN, IL-17 A, and anti-MBP auto-antibody levels in ASD group were not correlated with the scores of ABC, CARS, and PPVT(P>0.05). However, anti-MBP auto-antibodies level in children with ASD were positively correlated with OPN and IL-17 A levels, respectively(r=0.35, 0.34, P<0.05). Conclusion It was obvious that the ASD children were found with neuroimmunologic abnormality, and the underlying mechanism needs to be further explored.
Objective To explore the relationship among osteopontin(OPN), Interleukin-17 A(IL-17 A), anti-MBP auto-antibody and autism spectrum disorder(ASD), and to provide the theoretical basis for the etiology and pathogenesis of ASD. Methods Forty autistic children and forty matched healthy children were enrolled in this case-control study. The levels of OPN, IL-17 A, anti-MBP auto-antibody in serum were measured by enzyme-linked immunosorbent assay(ELISA). The associations between those metabolic levels and the severity and intelligence of ASD children were performed by Pearson or Spearman correlation. Results Children with ASD had higher serum levels of OPN, IL-17 A [(296.89±162.95),0.93] pg/mL compared to healthy control[(217.98±113.39), 0.62] pg/mL(P<0.05). Serum OPN, IL-17 A, and anti-MBP auto-antibody levels in ASD group were not correlated with the scores of ABC, CARS, and PPVT(P>0.05). However, anti-MBP auto-antibodies level in children with ASD were positively correlated with OPN and IL-17 A levels, respectively(r=0.35, 0.34, P<0.05). Conclusion It was obvious that the ASD children were found with neuroimmunologic abnormality, and the underlying mechanism needs to be further explored.
引文
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[3] MARTELETO M R,PEDROM?NICO M R.Validity of Autism Behavior Checklist (ABC):preliminary study[J].Brazl Psychiatr,2005,27(4):295-301.
[4] 杨玉凤,王惠珊,洪琦,等.儿童发育行为心理评定量表[M].北京:人民卫生出版社,2016:131-134.
[5] 王子才,钱冬梅,盛晓慰,等.用ABC量表分析儿童孤独症[J].临床儿科杂志,2002,20(2):80-81.
[6] EAVES R C,MILNER B.The criterion-related validity of the childhood autism rating scale and the autism behavior checklist[J].J Abnorm Child Psychol,1993,21(5):481-491.
[7] 卢建平,杨志伟,舒明辉,等.儿童孤独症量表评定的信度、效度分析[J].中国现代医学杂志,2004,14(13):119-121.
[8] 朱平,关广霞,王永霞,等.孤独症谱系障碍的免疫学研究进展[J].中国免疫学杂志,2016,32(4):588-590.
[9] SHINOHARA M L,LU L,BU J,et al.Osteopontin expression is essential for interferon-alpha production by plasmacytoid dendritic cells[J].Nature Immunol,2006,7(5):498-519.
[10] SHINOHARA M L,KIM H J,KIM J H,et al.Alternative translation of osteopontin generates intracellular and secreted isoforms that mediate distinct biological activities in dendritic cells[J].Proceed Nat Acad Sci United States Am,2008,105(20):7235-7239.
[11] SHINOHARA M L,KIM J H,GARCIA V A,et al.Engagement of the type I interferon receptor on dendritic cells inhibits T Helper 17 Cell development:role of intracellular osteopontin[J].Immunity,2008,29(1):68-89.
[12] BETTELLI E,CARRIER Y,GAO W,et al.Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J].Nature,2006,441(7090):235-238.
[13] MANGAN P R,HARRINGTON L E,O’ QUINN D B,et al.Transforming growth factor-beta induces development of the T(H)17 lineage[J].Nature,2006,441(7090):231-234.
[14] AL-AYADHI L Y,MOSTAFA G A.Elevated serum levels of interleukin-17A in children with autism[J].J Neuroimmund,2012,9(1):158-163.
[15] AL-AYADHI L Y,MOSTAFA G A.Increased serum osteopontin levels in autistic children:relation to the disease severity[J].Brain Behav Immun,2011,25(7):1393-1398.
[16] MOSTAFA G A,AL-AYADHI L Y.The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children[J].J Neuroimmunol,2013,261(1/2):77-81.
[17] MOSTAFA G A,EL-KHASHAB H Y,AL-AYADHI L Y.A possible association between elevated serum levels of brain-specific auto-antibodies and reduced plasma levels of docosahexaenoic acid in autistic children[J].J Neuroimmunol,2015,280:16-20.DOI:10.1016/j.jneuroim.2015.01.009.
[18] TETREAULT N A,HAKEEM A Y,JIANG S,et al.Microglia in the cerebral cortex in Autism[J].J Autism Dev Dis,2012,42(12):2569-2584.
[19] MOSTAFA G A,ALAYADHI L Y.A lack of association between hyperserotonemia and the increased frequency of serum anti-myelin basic protein auto-antibodies in autistic children[J].J Neuroinflammation,2011,8:71-78.
[20] MURUGAIYAN G,MITTAL A,WEINER H L.Increased osteopontin expression in dendritic cells amplifies IL-17 production by CD4+ T cells in experimental autoimmune encephalomyelitis and in multiple sclerosis[J].J Immunol,2008,181(11):7480-7488.
[21] AHMAD S F,ZOHEIR K M,ANSARI M A,et al.Dysregulation of Th1,Th2,Th17,and T regulatory cell-related transcription factor signaling in children with autism[J].Mol Neurobiol,2016,54(6):1-11.
[22] VOJDANI A,ANYANWU E,KASHANIAN A,et al.Antibodies to neuron-specific antigens in children with autism:possible cross-reaction with encephalitogenic proteins from milk,chlamydia pneumoniae,and streptococcus,group A[J].J Neuroimmunol,2002,129(1-2):168-177.
[23] CHEN M,CHEN G,NIE H,et al.Regulatory effects of IFN-beta on production of osteopontin and IL-17 by CD4+T cells in MS[J].Europ J Immunol,2010,39(9):2525-2536.
[24] HUR E M,YOUSSEF S,HAWS M E,et al.Osteopontin-induced relapse and progression of autoimmune brain disease through enhanced survival of activated T cells[J].Nat Immunol,2007,8(1):74-83.
[25] STROMNES I M,GOVERMAN J M.Osteopontin-induced survival of T cells[J].Nat Immunol,2007,8(1):19-20.