Abstract
Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1β), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFβ induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.
Conflict of interest statement
TCT has been awarded US Patents No 8268365; 9050275 and 9176146 covering treatment of brain inflammation and of ASD. He has developed the luteolin-containing dietary supplements BrainGain, NeuroProtek and NeuroProtek-low phenol. The remaining authors declare no conflicts of interest
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References
Lai MC, Lombardo MV, Baron-Cohen S. Autism. Lancet 2014; 383: 896–910. - PubMed
Volkmar FR, McPartland JC. From Kanner to DSM-5: autism as an evolving diagnostic concept. Annu Rev Clin Psychol 2014; 10: 193–212. - PubMed
Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res 2009; 65: 591–598. - PubMed
Geschwind DH, State MW. Gene hunting in autism spectrum disorder: on the path to precision medicine. Lancet Neurol 2015; 11: 1109–1120. - PMC - PubMed
Willsey AJ, State MW. Autism spectrum disorders: from genes to neurobiology. Curr Opin Neurobiol 2015; 30: 92–99. - PMC - PubMed