Children With Autism Spectrum Disorder and Their Mothers Share Abnormal Expression of Selected Endogenous Retroviruses Families and Cytokines
Children With Autism Spectrum Disorder and Their Mothers Share Abnormal Expression of Selected Endogenous Retroviruses Families and Cytokines
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DOI：
10.3389/fimmu.2019.02244
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发表时间：
2019-09-26
影响因子：
7.3
通讯作者：
Sinibaldi-Vallebona, Paola
中科院分区：
文献类型：
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作者：
Balestrieri, Emanuela;Cipriani, Chiara;Sinibaldi-Vallebona, Paola
自闭症谱系障碍（ASD）是一组异质性的神经发育障碍，由于缺乏可靠的生物标志物，只能在临床上诊断。自闭症的病因可能是由于遗传易感性和环境因素的结合，最近，母体免疫激活已被链接到脱轨的神经发育，导致自闭症的后代。人类内源性逆转录病毒（HERV）是祖先感染的遗物，稳定地整合在人类DNA中。考虑到HERV在基因组中的持久性，一些HERV在进化过程中被增选用于生理功能，而它们的再激活与几种病理状况相关，包括癌症、自身免疫性疾病以及神经和精神疾病。特别地，由于其对外部刺激的内在响应性，HERV可以调节宿主免疫应答，并且反过来HERV可以被免疫效应物激活。在以往的工作中，我们证明HERV-H在自闭症患者血液中的高表达水平，与疾病的严重程度密切相关。此外，在临床前ASD模型中，我们证明了几个ERV家族和细胞因子的表达从宫内生活到成年的变化，以及通过母体谱系的代际变化。在这里，我们分析了HEMO和选定的HERV和细胞因子在ASD患者及其父母和相应的健康对照血液中的表达，以寻找家庭成员中的共同分子特征。ASD患者和他们的母亲共享HERV-H和HEMO以及细胞因子如TNF-α、IFN-γ、IL-10的表达改变。多变量回归模型显示HEMO活性与母婴相关，并在儿童和母亲中证明HERV-H与HEMO表达之间存在关联，仅在母亲中，HEMO与TNF-α表达之间存在关联。此外，HERV-H和HEMO的高诊断性能被发现，这表明它们在ASD儿童及其母亲的识别中的潜在应用。目前的数据支持HERVs参与ASD，并建议HERVs和细胞因子作为ASD相关性状。由于ASD是一组异质性神经发育障碍，单独的单一决定因素可能不足以解释其复杂性，因此可以在一组生物标志物中考虑HERV/细胞因子表达，这些生物标志物易于在血液中检测，并可能用于早期诊断。
The Autism Spectrum Disorder (ASD) is a heterogeneous group of neurodevelopmental disorders, only clinically diagnosed since the lack of reliable biomarkers. Autism etiology is probably attributable to the combination of genetic vulnerability and environmental factors, and recently, maternal immune activation has been linked to derailed neurodevelopment, resulting in ASD in the offspring. Human endogenous retroviruses (HERVs) are relics of ancestral infections, stably integrated in the human DNA. Given the HERV persistence in the genome, some of HERVs have been co-opted for physiological functions during evolution, while their reactivation has been associated with several pathological conditions, including cancer, autoimmune, and neurological and psychiatric disorders. Particularly, due to their intrinsic responsiveness to external stimuli, HERVs can modulate the host immune response and in turn HERVs can be activated by the immune effectors. In previous works we demonstrated high expression levels of HERV-H in blood of autistic patients, closely related with the severity of the disease. Moreover, in a preclinical ASD model we proved changes of expression of several ERV families and cytokines from the intrauterine life to the adulthood, and across generations via maternal lineage. Here we analyzed the expression of HEMO and of selected HERVs and cytokines in blood from ASD patients and their parents and corresponding healthy controls, to look for a common molecular trait within family members. ASD patients and their mothers share altered expression of HERV-H and HEMO and of cytokines such as TNF-alpha, IFN-gamma, IL-10. The multivariate regression models showed a mother-child association by HEMO activity and demonstrated in children and mothers an association between HERV-H and HEMO expression and, only in mothers, between HEMO, and TNF-alpha expression. Furthermore, high diagnostic performance for HERV-H and HEMO was found, suggesting their potential application for the identification of ASD children and their mothers. The present data support the involvement of HERVs in ASD and suggest HERVs and cytokines as ASD-associated traits. Since ASD is a heterogeneous group of neurodevelopmental disorders, a single determinant alone could be not enough to account for the complexity, and HERV/cytokines expression could be considered in a set of biomarkers, easily detectable in blood, and potentially useful for an early diagnosis.