The Impact of Neuroimmune Alterations in Autism Spectrum Disorder

Abstract

Autism spectrum disorder (ASD) involves a complex interplay of both genetic and environmental risk factors, with immune alterations and synaptic connection deficiency in early life. In the past decade, studies of ASD have substantially increased, in both humans and animal models. Immunological imbalance (including autoimmunity) has been proposed as a major etiological component in ASD, taking into account increased levels of pro-inflammatory cytokines observed in postmortem brain from patients, as well as autoantibody production. Also, epidemiological studies have established a correlation of ASD with family history of autoimmune diseases; associations with major histocompatibility complex haplotypes and abnormal levels of immunological markers in the blood. Moreover, the use of animal models to study ASD is providing increasing information on the relationship between the immune system and the pathophysiology of ASD. Herein, we will discuss the accumulating literature for ASD, giving special attention to the relevant aspects of factors that may be related to the neuroimmune interface in the development of ASD, including changes in neuroplasticity.

Keywords: autism; environmental risk factors; neuroimmune interactions; rodent models; valproic acid.

Figure 1

Evidence for neuroimmune interactions in autism spectrum disorder (ASD). Blood and postmortem brain alterations in individuals with ASD. (1) Antibody production in blood against brain antigens. (2) Brain cell infiltration of Th1 lymphocytes, monocytes and mast cells. (3) Increase in blood brain barrier (BBB) permeability. (4) Increase in IgG and IgM levels. (5) Less antioxidant defenses. (6) Changes in cytokine levels. (7) Decrease in cell adhesion molecules, such as Selectins and PCAM-1. 8. Increase in oxidative stress. All these alterations can promote neuroinflammation, followed by neuron–glial response and brain connectivity dysfunction that ultimately can influence behavioral features in ASD. GSH, glutathione; GPx, glutathione peroxidase; NO, nitric oxide; Th, T-helper; OS, oxidative stress; CCL2, C–C motif chemokine 2.

Figure 2

Hypothesis for neuroimmune interactions in triggering the development of ASD. This hypothesis considers the presence of environmental risk factors during pregnancy, followed by immunoneuroendocrine response from the mother to the developing embryo/fetus. The risk factors (such as VPA) would influence central and peripheral neural responses in the context of a crosstalk with the immune system, followed by gradual changes in neural plasticity and function, resulting in behavioral impairment during development, ultimately leading to ASD.