Mast cells disrupt the gut-blood-brain barriers and contribute to autism by Theoharis Theoharides, MD, PhD

Many autism spectrum disorder (ASD) patients have a history of "allergic" symptoms and food intolerance, suggesting activation of mast cells, now recognized as master regulators of the immune system. Activation of intestinal and brain mast cells by immune, infectious, stress or toxic triggers could lead to gut-blood-brain-barrier disruption, permitting brain inflammation and autism. This is more likely to occur in children up to 3 years old, who are more susceptible to infections, and when their gut-blood-brain barriers are still developing. Moreover, perinatal stress has been associated with ASD development, and we have shown that corticotropin-releasing hormone (CRH) secreted under stress and during premature labor can induce mast cells to release vascular endothelial growth factor (VEGF), which increases blood-brain-barrier permeability. We have also shown that mercury causes release of VEGF from human mast cells. Mast cells are critical in the disease mastocytosis, characterized by an increased number of hypersensitive mast cells in many tissues. Children with mastocytosis also present with skin allergies, diarrhea, learning disabilities, hyperactivity and difficulty focusing, reminiscent of ASD. A survey of the Mastocytosis Society's members (www.tsmforacure.org) indicated that the rate of autism in children with mastocytosis is at least 10-fold higher than that reported for the general population. Mastocytosis patients also have high blood levels of interleukin-6 (IL-6), which has recently been implicated in an "animal model" of autism, and which we have shown derives entirely from mast cells. We have also shown that the naturally occurring flavonoids luteolin and quercetin can inhibit human mast cell release of IL-6 and other inflammatory molecules.

Theoharis Theoharides, MD, PhD is a professor of pharmacology, Internal Medicine and Biochemistry, and the director of the Laboratory of Molecular Immunopharmacology and Drug Discovery; Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine. He trained in allergy and clinical immunology at Yale and internal medicine at New England Medical Center. Dr. Theoharides was director of medical pharmacology at Tufts (1986-1993), and became full professor in 1995. He has 300 publications and 3 books, including a Textbook of Pharmacology. Dr. Theoharides was the first to show mast cells and acute stress promote inflammation in autism, cancer, interstitial cystitis, migraines and multiple sclerosis.