Brain Fires in Autism Spectrum Disorders

Theoharides TC, Stewart JM,

Abstract

Autism spectrum disorders (ASD) is characterized by social and communicative deficits, severe anxiety, and stereotypic movements. Despite affecting as many as 1 in 45 US children in the USA, the pathogenesis of ASD is still unknown. Recent epidemiological studies indicated a strong statistical correlation between risk for maternal / infant atopic diseases and ASD suggesting the possible involvement and activation of mast cells (MC). These unique immune cells are located close to blood vessels in all tissues, including the thalamus and hypothalamus in the brain, which regulate emotions known to be dysfunctional in ASD. Moreover, MCs are stimulated by two brain peptides, corticotropin-releasing hormone (CRH) and neurotensin (NT), which we showed to be high in the blood of children with ASD. Stimulated MCs then secrete inflammatory molecules that activate brain microglia, which proliferate and “choke off” nerve communication. These inflammatory molecules are increased in the brain and serum of patients with ASD and also lead to disruption of the protective blood brain barrier (BBB), which is regulated by MCs, permitting the entry of circulating white blood cells and toxins contributing to brain. We further reported that the elevated blood levels of two inflammatory molecules, IL-6 and TNF, identify a subgroup of children with ASD, who benefit most from a promising treatment with the natural flavonoid luteolin that combats brain inflammation. Extinguishing inflammation (“Brain fires”) may be the best hope for curing ASD.