Review

BMC Pediatrics

, 12:89

Open Access This content is freely available online to anyone, anywhere at any time.

Perinatal stress, brain inflammation and risk of autism-Review and proposal

  • Asimenia AngelidouAffiliated withMolecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical CenterAllergy Clinical Research Center, Allergy Section, Attikon General Hospital, Medical SchoolDepartment of Pediatrics, University of Texas Southwestern, Childrens Medical Center Email author 
  • , Shahrzad AsadiAffiliated withMolecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical CenterDepartment of Pharmacy, Tufts Medical Center Email author 
  • , Konstantinos-Dionysios AlysandratosAffiliated withMolecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical CenterAllergy Clinical Research Center, Allergy Section, Attikon General Hospital, Medical SchoolDepartment of Internal Medicine, University of Texas Southwestern Medical Center
  • , Anna KaragkouniAffiliated withMolecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical Center
  • , Stella KourembanasAffiliated withDivision of Newborn Medicine, Children’s Hospital Boston, Harvard Medical School
  • , Theoharis C TheoharidesAffiliated withMolecular Immunopharmacology and Drug Discovery Laboratory, Department of Molecular Physiology and Pharmacology, Tufts University School of Medicine and Tufts Medical CenterDepartment of Biochemistry, Tufts University School of Medicine and Tufts Medical CenterDepartment of Internal Medicine, Tufts University School of Medicine and Tufts Medical CenterDepartment of Psychiatry, Tufts University School of Medicine and Tufts Medical CenterAllergy Clinical Research Center, Allergy Section, Attikon General Hospital, Medical School Email author 

Abstract

Background

Autism Spectrum Disorders (ASD) are neurodevelopmental disorders characterized by varying deficits in social interactions, communication, and learning, as well as stereotypic behaviors. Despite the significant increase in ASD, there are few if any clues for its pathogenesis, hampering early detection or treatment. Premature babies are also more vulnerable to infections and inflammation leading to neurodevelopmental problems and higher risk of developing ASD. Many autism “susceptibility” genes have been identified, but “environmental” factors appear to play a significant role. Increasing evidence suggests that there are different ASD endophenotypes.

Discussion

We review relevant literature suggesting in utero inflammation can lead to preterm labor, while insufficient development of the gut-blood–brain barriers could permit exposure to potential neurotoxins. This risk apparently may increase in parents with “allergic” or autoimmune problems during gestation, or if they had been exposed to stressors. The presence of circulating auto-antibodies against fetal brain proteins in mothers is associated with higher risk of autism and suggests disruption of the blood–brain-barrier (BBB). A number of papers have reported increased brain expression or cerebrospinal fluid (CSF) levels of pro-inflammatory cytokines, especially TNF, which is preformed in mast cells. Recent evidence also indicates increased serum levels of the pro-inflammatory mast cell trigger neurotensin (NT), and of extracellular mitochondrial DNA (mtDNA), which is immunogenic. Gene mutations of phosphatase and tensin homolog (PTEN), the negative regulator of the mammalian target of rapamycin (mTOR), have been linked to higher risk of autism, but also to increased proliferation and function of mast cells.

Summary

Premature birth and susceptibility genes may make infants more vulnerable to allergic, environmental, infectious, or stress-related triggers that could stimulate mast cell release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in an endophenotype of ASD patients.

Keywords

Allergy Autism Brain Inflammation Mast cells Prematurity Stress