Oxidative Stress and Immune System Dysfunction in Autism Spectrum Disorders

Luca Pangrazzi,Yuri Bozzi,Luigi Balasco

doi:10.3390/ijms21093293

Luca Pangrazzi, Yuri Bozzi + Show 1 more

Open Access

https://doi.org/10.3390/ijms21093293

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Abstract

Autism Spectrum Disorders (ASDs) represent a group of neurodevelopmental disorders associated with social and behavioral impairments. Although dysfunctions in several signaling pathways have been associated with ASDs, very few molecules have been identified as potentially effective drug targets in the clinic. Classically, research in the ASD field has focused on the characterization of pathways involved in neural development and synaptic plasticity, which support the pathogenesis of this group of diseases. More recently, immune system dysfunctions have been observed in ASD. In addition, high levels of reactive oxygen species (ROS), which cause oxidative stress, are present in ASD patients. In this review, we will describe the major alterations in the expression of genes coding for enzymes involved in the ROS scavenging system, in both ASD patients and ASD mouse models. In addition, we will discuss, in the context of the most recent literature, the possibility that oxidative stress, inflammation and immune system dysfunction may be connected to, and altogether support, the pathogenesis and/or severity of ASD. Finally, we will discuss the possibility of novel treatments aimed at counteracting the interplay between ROS and inflammation in people with ASD.

Highlights

Autism Spectrum Disorders (ASD) form a heterogeneous group of neurodevelopmental syndromes characterized by persistent deficits in social communication and social interaction, and restricted, repetitive patterns of behavior, interests or activities [1]
The pro-inflammatory cytokine IL-6 appears to play a key role in all the above mentioned models, and exposure to IL-6 alone during gestation was reported to be sufficient to elicit behavioral changes in the offspring [66,67]. These results suggest that the increased production of pro-inflammatory molecules in ASD may represent a strong contributor to the pathogenesis and the severity of these disorders
It is becoming evident that antioxidants and vitamins, taken as supplements or included in foods, may strongly help ASD persons in attenuating their ASD-associated symptoms. It is becoming clearer how immune system dysfunctions may be associated with ASD

Summary

Introduction

Autism Spectrum Disorders (ASD) form a heterogeneous group of neurodevelopmental syndromes characterized by persistent deficits in social communication and social interaction, and restricted, repetitive patterns of behavior, interests or activities [1]. According to the AutDB database (http://autism.mindspec.org/autdb/Welcome.do, updated January 2020), 3145 animal models of ASD, including inbred, induced and genetic mouse models, are currently available. Genetic studies demonstrated that mutations in several genes coding for synaptic proteins, such as SHANK3 [2], NLGN3, NLGN4X [3], CNTNAP2 [4] and GABRB3 [5], are associated with ASD. Several genes associated with ASD, such as PTEN, TSC1 and TSC2, all involved in the phosphoinositide-3-kinase (PI3K) pathway, display immunoregulatory functions. We first summarize recent literature discussing the contribution of oxidative stress to ASD. We will discuss about how oxidative stress may be linked to neuroinflammation, contributing to an ASD-like phenotype. We will summarize the results of some studies, in which interventions using antioxidants as supplements or included in foods led to improvements in ASD symptoms

The Contribution of Oxidative Stress to ASD

Oxidative Stress in Human ASD Samples and Mouse Models: A Meta-Analysis

Targeting ROS to Treat ASD

Conclusions