Abstract
The prevalence of autism spectrum disorder (ASD) has starkly increased, instigating research into risk factors for ASD. This research has identified immune risk factors for ASD, along with evidence of immune dysfunction and excess inflammation frequently experienced by autistic individuals. Increased innate inflammatory cytokines, including interleukin (IL)-6, are seen repeatedly in ASD; however, the origin of excess IL-6 in ASD has not been identified. Here we explore specific responses of circulating monocytes from autistic children. We isolated CD14+ monocytes from whole blood and stimulated them for 24 h under three conditions: media alone, lipoteichoic acid to activate TLR2, and lipopolysaccharide to activate TLR4. We then measured secreted cytokine concentrations in cellular supernatant using a human multiplex bead immunoassay. We found that after TLR4 activation, CD14+ monocytes from autistic children produce increased IL-6 compared to monocytes from children with typical development. IL-6 concentration also correlated with worsening restrictive and repetitive behaviors. These findings suggest dysfunctional activation of myeloid cells, and may indicate that other cells of this lineage, including macrophages, and microglia in the brain, might have a similar dysfunction. Further research on myeloid cells in ASD is warranted.
Highlights
Autism spectrum disorder (ASD) is a heterogenous disorder characterized by impairments in social interactions and communication, accompanied by restricted and repetitive behaviors of varying degrees [1]
We found that after TLR4 stimulation, IL-6 production was significantly increased in ASD monocytes, and this increase was associated with repetitive behaviors
Participants were clinically evaluated for placement into one of two diagnostic groups, with final diagnosis confirmed by the Autism Diagnostic Interview-Revised (ADI-R) [35] and the Autism Diagnostic Observation Schedule (ADOS) [36]: (1) children diagnosed with ASD [n = 25, 19M/6F, median age 5.62 years]; or (2) children with typical development (TD) [n = 20, 16M/4F, 5.48 (4.86–6.13) years]
Summary
Autism spectrum disorder (ASD) is a heterogenous disorder characterized by impairments in social interactions and communication, accompanied by restricted and repetitive behaviors of varying degrees [1]. An alarming increase in the prevalence of ASD has occurred over the past several decades. Recent estimation of this prevalence is currently 1 in 59 children, with males having a significantly higher prevalence than females [1]. Substantial comorbidities are seen in ASD, including gastrointestinal dysfunction, seizures, and sleep disorders [2]. These contribute to decreasing quality of life for autistic individuals; identifying and treating biological factors driving these complex disorders could help alleviate some of these morbidities and improve outcomes for autistic individuals and their families. One biological factor that has been hypothesized as contributing to the etiology and pathophysiology of ASD is immune system abnormalities that may be driving deviant neuroimmune responses [3]
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