PMID- 23688533
OWN - NLM
STAT- MEDLINE
DCOM- 20131230
LR  - 20130521
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 35
IP  - 5
DP  - 2013 May
TI  - Is a subtype of autism an allergy of the brain?
PG  - 584-91
LID - S0149-2918(13)00182-3 [pii]
LID - 10.1016/j.clinthera.2013.04.009 [doi]
AB  - BACKGROUND: Autism spectrum disorders (ASDs) are characterized by deficits in 
      social communication and language and the presence of repetitive behaviors that 
      affect as many as 1 in 50 US children. Perinatal stress and environmental factors 
      appear to play a significant role in increasing the risk for ASDs. There is no 
      definitive pathogenesis, which therefore significantly hinders the development of 
      a cure. OBJECTIVE: We aimed to identify publications using basic or clinical data 
      that suggest a possible association between atopic symptoms and ASDs, as well as 
      evidence of how such an association could lead to brain disease, that may explain 
      the pathogenesis of ASD. METHODS: PubMed was searched for articles published 
      since 1995 that reported any association between autism and/or ASDs and any one 
      of the following terms: allergy, atopy, brain, corticotropin-releasing hormone, 
      cytokines, eczema, food allergy, food intolerance, gene mutation, inflammation, 
      mast cells, mitochondria, neurotensin, phenotype, stress, subtype, or treatment. 
      RESULTS: Children with ASD respond disproportionally to stress and also present 
      with food and skin allergies that involve mast cells. Brain mast cells are found 
      primarily in the hypothalamus, which participates in the regulation of behavior 
      and language. Corticotropin-releasing hormone is secreted from the hypothalamus 
      under stress and, together with neurotensin, stimulates brain mast cells that 
      could result in focal brain allergy and neurotoxicity. Neurotensin is 
      significantly increased in serum of children with ASD and stimulates mast cell 
      secretion of mitochondrial adenosine triphosphate and DNA, which is increased in 
      these children; these mitochondrial components are misconstrued as innate 
      pathogens, triggering an autoallergic response in the brain. Gene mutations 
      associated with higher risk of ASD have been linked to reduction of the 
      phosphatase and tensin homolog, which inhibits the mammalian target of rapamycin 
      (mTOR). These same mutations also lead to mast cell activation and proliferation. 
      Corticotropin-releasing hormone, neurotensin, and environmental toxins could 
      further trigger the already activated mTOR, leading to superstimulation of brain 
      mast cells in those areas responsible for ASD symptoms. Preliminary evidence 
      indicates that the flavonoid luteolin is a stronger inhibitor of mTOR than 
      rapamycin and is a potent mast cell blocker. CONCLUSION: Activation of brain mast 
      cells by allergic, environmental, immune, neurohormonal, stress, and toxic 
      triggers, especially in those areas associated with behavior and language, lead 
      to focal brain allergies and subsequent focal encephalitis. This possibility is 
      more likely in the subgroup of patients with ASD susceptibility genes that also 
      involve mast cell activation.
CI  - Copyright (c) 2013 Elsevier HS Journals, Inc. All rights reserved.
FAU - Theoharides, Theoharis C
AU  - Theoharides TC
AD  - Molecular Immunopharmacology and Drug Discovery Laboratory, Department of 
      Molecular Physiology and Pharmacology, Tufts University School of Medicine, 
      Boston, MA 02111, USA. theoharis.theoharides@tufts.edu
LA  - eng
GR  - AR47652/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
SB  - IM
MH  - Animals
MH  - Autistic Disorder/epidemiology/etiology/*immunology
MH  - Brain/*immunology/physiopathology
MH  - Child
MH  - Child Development Disorders, Pervasive/epidemiology/etiology/immunology
MH  - Food Hypersensitivity/epidemiology
MH  - Genetic Predisposition to Disease
MH  - Humans
MH  - Hypersensitivity/*complications/immunology
MH  - Mast Cells/metabolism
MH  - Stress, Psychological/epidemiology
EDAT- 2013/05/22 06:00
MHDA- 2014/01/01 06:00
CRDT- 2013/05/22 06:00
PHST- 2013/04/04 00:00 [received]
PHST- 2013/04/19 00:00 [revised]
PHST- 2013/04/19 00:00 [accepted]
PHST- 2013/05/22 06:00 [entrez]
PHST- 2013/05/22 06:00 [pubmed]
PHST- 2014/01/01 06:00 [medline]
AID - S0149-2918(13)00182-3 [pii]
AID - 10.1016/j.clinthera.2013.04.009 [doi]
PST - ppublish
SO  - Clin Ther. 2013 May;35(5):584-91. doi: 10.1016/j.clinthera.2013.04.009.