Mast cells, microglia and brain inflammation

Promising treatment pathways for autism… 

Autism Spectrum Disorders (ASD) are pervasive developmental disorders for which there are no distinct pathogenesis, no biomarkers and few effective treatments.  The diagnosis of ASD has increased more than 10-fold during the last decade to 1/150 children, and more recently to about 1/88 children (http://www.cdc.gov/Features/CountingAutism/).

ASDs involve some immune dysfunction, and  many children with ASD also have atopic features, food allergies and other “allergic-like” symptoms, suggesting mast cell activation by non-allergic triggers.

Unique immune cells

Mast cells are unique immune cells present in all tissues; they are mostly found in the dienchepalon of the brain that controls emotions. Mast cells act as “alarmins” to environmental, infectious and stress insults. Moreover, children with mastocytosis, a spectrum of diseases that present with gastrointestinal and skin allergies, appear to have a 10-fold higher prevalence of ASD (1/10) than what is reported for the general population. 

Along with my fellow researchers, I believe that ASD is a neurological disease derived from perinatal auto-immune insults to specific brain areas leading to local encephalopathy. We recently published that neurotensin (NT), a peptide found in the brain and the gut, is increased in the serum of young children with autism. Intestinal mast cells can also be activated by NT, a potent neuropeptide that is abundant in the gut. It is interesting that distribution of NT receptors is more concentrated in the brain diencephalon and the Broca area, which regulates speech, commonly lost or impaired in children with autism.

Synergistic actions

Many mothers of ASD children along with ASD children have serum autoantibodies to brain protein implying disruption of the blood-brain-barrier (BBB). Mast cells are critically located around the BBBand their activation leads to BBB disruption.

In a 2006 study, we showed that corticotropin-releasing hormone (CRH), secreted under stress, can stimulate mast cells through a synergistic action with NT to increase vascular permeability and disrupt the BBB. Moreover, CRH also increases allergic stimulation of human mast cells.

Cell injury sensors

Mast cells have been considered “sensors of cell injury” through IL-33, but also through secretion of mitochondrial components extracellularly that can further stimulate mast cells and other immune cells. We also showed that serum of the same ASD children has increased amounts of mitochondrial DNA (mtDNA) and that NT-activated human cultured mast cells can secrete mtDNA measured by real time PCR.

Recent evidence also indicates that abnormal growth of microglial cells may be involved in autism. Microglial cells express neurotensin receptor-3 (NTR3) leading to their proliferation. Mast cell-microglial interactions are considered important in neuroinflammation and molecules such as CRH, NT and IL-33 could also regulate such interactions.

Therapeutic Implications

The total annual cost of ASD is now $126 billion in the USA, £ 34 billion in the UK and is expected to grow 12% per year (http://www.autismspeaks.org/about-us/press-releases/annual-cost-of-autism-triples). It costs $3.2 million for the life-long care and treatment of each ASD patient. Our proposal addresses the use of CRH and NT:

  1. as critical components of ASD pathogenesis
  2. as potential biomarkers that could be used for diagnostic purposes
  3. as targets for novel treatments using CRH and NT receptor antagonists

Moreover, mast cell and microglial inhibitors, especially those blocking the effect of NT may serve as novel therapeutic agents for the treatment of ASD.  For instance, a recent paper reported that the flavonoid resveratrol inhibits inflammatory responses in murine microglial cells. We had reported that the related flavonoid luteolin can inhibit mercury-induced mast cell activation. We also recently reported that a luteolin containing dietary formulation had beneficial effects in ASD.

Luteolin has numerous properties that may be useful in ASD: it is

  • anti-oxidant
  • anti-inflammatory
  • mast cell degranulation inhibitor
  • mast cell cytokine release inhibitor
  • thimerosal-induced inflammatory mediator release inhibitor
  • microglial activation inhibitor
  • inhibitor of auto-immune T cell activation
  • protective against methylmercury-induced mitochondrial damage
  • neuroprotective
  • able to reverse ASD behavior in mice

Luteolin is generally safe, and can even protect against chemically-induced hepatotoxicity.  Parents and caregivers should consult with their physicians to determine if Luteolin should be considered as part of an autism treatment protocol.

 

Theoharis C. Theoharides, MS, PhD, MD, FAAAAI. Dr. Theoharides is the Director of the Molecular Immunopharmacology and Drug Discovery Laboratory, as well as a Professor of Pharmacology, Biochemistry and Internal Medicine at Tufts University, Boston, MA. He received all his degrees from Yale University and was awarded the Winternitz Price in Pathology. Dr. Theoharides has a Certificate in Global Leadership and Management from the Fletcher School of Law and Diplomacy at Tufts University and was selected Kennedy Fellow for an MPA at the J.F. Kennedy School of Government, Harvard University. Dr. Theoharides served on the Research Faculty of Allergy and Immunology at Yale before training in internal medicine at New England Medical Center (NEMC) in Boston.  He joined Tufts University in 1983 and became a tenured, full professor in 1995. He helped develop the Department and graduate studies in Pharmacology and Experimental Therapeutics, and was the Director of Medical Pharmacology (1986-1993). He has served on 10 different NIH Study Sections, and has trained over 100 high school, college, medical, graduate and post-doctorate students.

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