Abstract
BackgroundMicroRNAs (miRNAs) play a major role in regulating immune responses at post-transcriptional levels. Previously, we have reported fluctuating interlukine-1ß (IL-1ß)/IL-10 ratios produced by peripheral blood monocytes (PBMo) in some patients with autism spectrum disorders (ASD). This study examined whether changes in miRNA expression by PBMo are associated with changes in IL-1ß/IL-10 ratios and how such changes are associated with ASD clinical features.MethodsmiRNA expression by purified PBMo from ASD subjects (N = 69) and non-ASD controls (N = 27) were determined by high-throughput sequencing. Cytokine production by PBMo in responses to stimuli of innate immunity, and behavioral symptoms [assessed by aberrant behavioral checklist (ABC)] were also evaluated at the same time of sample obtainment.ResultsAs a whole, there was no difference in miRNA expression between ASD and control non-ASD PBMo. However, when ASD cells were subdivided into 3 groups with high, normal, or low IL-1ß/IL-10 ratios as defined in the “Results” section, in comparison with the data obtained from non-ASD controls, we observed marked changes in miRNA expression. Namely, over 3-fold changes in expression of miR-181a, miR-93, miR-223, miR-342, and miR-1248 were observed in ASD PBMo with high or low IL-1ß/IL-10 ratios, but not in ASD PBMo with normal ratios. These miRNAs that had altered in expression are those closely associated with the regulation of key signaling pathways. With changes in IL-1ß/IL-10 ratios, we also observed changes in the production of cytokines (IL-6, TNF-α, and TGF-ß) other than IL-1ß/IL-10 by ASD PBMo. The association between behavioral symptoms and cytokine levels was different when ASD cells exhibit high/low IL-1ß/IL-10 ratios vs. when ASD cells exhibited normal ratios. Non-IgE-mediated food allergy was also observed at higher frequency in ASD subjects with high/low IL-1ß/IL-10 ratios than with normal ratios.ConclusionsChanges in cytokine profiles and miRNA expression by PBMo appear to be associated with changes in ASD behavioral symptoms. miRNAs that are altered in expression in ASD PBMo with high/low IL-1ß/IL-10 ratios are those associated with inflammatory responses. Changes in IL-1ß/IL-10 ratios along with changes in miRNA expression may serve as biomarkers for immune-mediated inflammation in ASD.
Highlights
MicroRNAs play a major role in regulating immune responses at post-transcriptional levels
Changes in cytokine profiles and miRNA expression by peripheral blood monocytes (PBMo) appear to be associated with changes in Autism spectrum disorder (ASD) behavioral symptoms. miRNAs that are altered in expression in ASD PBMo with high/low IL-1ß/IL-10 ratios are those associated with inflammatory responses
Fluctuating IL-1ß/IL-10 ratios in ASD PBMo were observed in some ASD subjects, a finding that is consistent with our previous study [25]
Summary
MicroRNAs (miRNAs) play a major role in regulating immune responses at post-transcriptional levels. We have reported fluctuating interlukine-1ß (IL-1ß)/IL-10 ratios produced by peripheral blood monocytes (PBMo) in some patients with autism spectrum disorders (ASD). Autism spectrum disorder (ASD) is a behaviorally defined syndrome, encompassing markedly heterogeneous subjects. In addition to their core behavioral symptoms, ASD patients frequently suffer from various co-morbid conditions. The presence of co-morbid conditions can affect ASD behavioral symptoms, partly through pain and discomfort [3, 4]. The presence of multiple co-morbid inflammatory conditions affecting organs other than the brain may be a clue in understanding the versatile clinical features exhibited by some ASD subjects. Since most inflammatory conditions are mediated by the immune system, such ASD patients as described above may have underlying immune-mediated inflammation, affecting both the brain and other organs. It has been difficult to elucidate how the immune system plays a role in ASD pathogenesis, since there are many immune abnormalities reported in ASD, affecting almost every arm of the immune system [6, 7]
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