Profiling of activated monocyte populations in autism and associations with increased severity and comorbid behaviors

Abstract

Immune dysfunction in autism spectrum disorder (ASD) has been widely reported and is associated with increased impairments in social interactions, communication, repetitive behaviors, anxiety and gastrointestinal problems. Several lines of evidence point towards increased activation of the innate immune system including activation of microglia, increases in innate inflammatory cytokines/chemokines in blood, brain tissue and CSF, activated dendritic cells and macrophages, and abnormal peripheral monocyte cell function. Monocytes are major players in innate immunity and have important functions in the phagocytosis of pathogens or debris, immune defense and cytokine/chemokine production. However, little is known about the frequencies of different circulating monocytes populations in ASD compared with similarly aged typically developing (TD) controls. In this study, the profile of circulating monocytes exhibiting different markers of activation were assessed in 77 children with ASD, and 49 TD controls who were enrolled as part of the Autism Phenome Project and were of a similar age, 2-4 years old. The frequencies of monocytes expressing the activation marker CD137 (4-1BB) were significantly increased in children with ASD and associated with greater behavioral impairments. In addition, although the frequencies of non-classical monocytes (CD14⁺CD16⁺) were not significantly different across groups, they were linked to worse behaviors in both the context of ASD and TD. Conversely classical monocytes were associated with better behavioral outcomes. These data further implicate monocytes and innate immune cells in the complex pathophysiology of ASD. Monocyte cells play key roles in modulating immune responses and differences in the activation profiles of these cells may result in immune dysfunction in children with ASD.

Keywords: ADOS; Autism; Autism Spectrum Disorder (ASD); Autism severity; Behaviors; CD137; Classical monocytes; Co-stimulation; Immunity; Innate immunity; Monocytes; Neurodevelopmental disorders; Neuroimmune; Non-classical monocytes.