Cytokine dysregulation in autism spectrum disorders (ASD): Possible role of the environment

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental diseases that affect an alarming number of individuals. The etiological basis of ASD is unclear, and evidence suggests it involves both genetic and environmental factors. There are many reports of cytokine imbalances in ASD. These imbalances could have a pathogenic role, or they may be markers of underlying genetic and environmental influences. Cytokines act primarily as mediators of immunological activity, but they also have significant interactions with the nervous system. They participate in normal neural development and function, and inappropriate activity can have a variety of neurological implications. It is therefore possible that cytokine dysregulation contributes directly to neural dysfunction in ASD. Further, cytokine profiles change dramatically in the face of infection, disease, and toxic exposures. Therefore, imbalances may represent an immune response to environmental contributors to ASD. The following review is presented in two main parts. First, we discuss select cytokines implicated in ASD, including IL-1Β, IL-6, IL-4, IFN-γ, and TGF-Β, and focus on their role in the nervous system. Second, we explore several neurotoxic environmental factors that may be involved in the disorders, and focus on their immunological impacts. This review represents an emerging model that recognizes the importance of both genetic and environmental factors in ASD etiology. We propose that the immune system provides critical clues regarding the nature of the gene by environment interactions that underlie ASD pathophysiology.

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“…The three SCFAs produced by the intestinal bacteria are acetic acid, propionic acid and butyric acid. SCFAs are important for the health and regulation of the intestinal membrane integrity and the development of innate and adaptive immune responses [2,6,12,18,19]. The gut microbiome is mainly shaped during the first months of life by different factors, including vaginal delivery, the host's genome, breastfeeding or formula feeding, use of antibiotics, GI infections and stress [2,19].…”

“…The gut microbiota is known to regulate brain activity and homeostasis of microglia through the immune system [2,12,13,18,41,44]. Microglia cells are a type of macrophage acting as the first immune defense in the brain.…”

“…Several concerns might exist, including the risk of nutritional deficiencies due to a decreased protein intake [2,12,74]. However, Johnson et al, [50] conducted a study of 3 months on the effects of the GFCF diet in young children with ASD.…”

“…Several dysregulated immune responses occur in ASD such as increased natural killer cell activity, the presence of autoantibodies directed against brain proteins, and altered cytokine profiles, leading a.o. to increased rate of middle ear infections at young age [2,12,13]. In addition, there is an increased prevalence of immune-mediated disorders in family members of children with ASD, including rhinitis, food allergy, and psoriasis and possibly even inflammatory bowel disease [10,14,15].…”

Aberrant IgG isotype generation in mice with abnormal behaviors

“…Although the etiology of autism is uncertain, its occurrence is continuously increasing to a prevalence level of almost 1% in children (Baird et al, 2006;CDC, 2012). The interaction of certain toxicants with brain tissue has recently been hypothesized to induce neuroinflammation associated with an ASD phenotype (Goines & Ashwood, 2013;Schwartzer et al, 2013). Thus, development of an appropriate animal model is necessary to allow researchers to better investigate the etiology/ pathogenesis of autism.…”