Review

Citation: Translational Psychiatry (2016) 6, e844; doi:10.1038/tp.2016.77
Published online 28 June 2016

Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders
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T C Theoharides1,2,3,4, I Tsilioni1, A B Patel1,2 and R Doyle5

  1. 1Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, Boston, MA, USA
  2. 2Sackler School of Graduate Biomedical Sciences, Program in Cell, Molecular and Developmental Biology, Tufts University, Boston, MA, USA
  3. 3Department of Internal Medicine, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA
  4. 4Department of Psychiatry, Tufts University School of Medicine and Tufts Medical Center, Boston, MA, USA
  5. 5Department of Child Psychiatry, Harvard Medical School, Massachusetts General Hospital and McLean Hospital, Boston, MA, USA

Correspondence: Professor TC Theoharides, Molecular Immunopharmacology and Drug Discovery Laboratory, Department of Integrative Physiology and Pathobiology, Tufts University School of Medicine, 136 Harrison Avenue, Suite J304, Boston, MA 02111, USA. E-mail: theoharis.theoharides@tufts.edu

Received 13 January 2016; Revised 23 February 2016; Accepted 17 March 2016

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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, 1L-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.