Autism and Mast
Cells
Spencer Martin, Peter Gao, Chris
Chiu and Faizan Baig
PHM142 Fall 2015
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
What is Autism?
- neurodevelopmental disorder
- environmental and genetic factors as probable cause
- social impairments
- communication impairment
- repetitive behaviours or interests
- symptoms appear around age 3
- still not well understood
http://asddad.com/wp-content/uploads/2012/03/autism-disorder1.jpg
Demographics of Autism
- affects ~ 21.7 million people
- rates increasing? or methods of diagnoses changing?
- averages 4.3 males to 1 female
- non-genetic factors
- pre-natal
- post-natal
What are Mast Cells?
-
-
part of the immune system
contains granules, including histamine and heparin
histamine is more commonly known for allergic responses
various ways of being stimulated to degranulate (mediators stored inside)
- IgE receptor linkage
- physical injury
- pathogens
- associated GPCRs
during an allergic reaction, the cell will be inactive until the allergen binds to
the IgE on the cell membrane
Mast Cells and Autism
Genetic Susceptibility
More than 100 genetic mutations causally implicated in ASD
Of particular interest: The PTEN and TSC1/2 gene mutations lead to
hyperactive mTOR signalling
This could lead to uninhibited over-activation and proliferation of mast cells and
thus susceptibility to ASD
Research suggests epigenetic and environmental interactions may play a role
Allergic/Immune Dysregulation
Activates
Mast Cells
Increased allergic problems and symptoms such as atopic dermatitis and
asthma is associated with certain ASD conditions.
The role of pro-inflammatory molecules (IL-12, IL-6, IFNg, TNF) is increased in
autism
Both viruses and bacterial LPS can activate mast cells
Asthma, hay fever and atopic dermatitis in mothers during second trimester of
pregnancy are correlated with more than double the risk of ASD in children
Non-Immune Mast Cell Triggers
➔Mast cell activation can result in brain inflammation:
1. Neurotensin (NT) stimulates mast cell secretion of mtDNA
a. mtDNA and NT are significantly increased in serum of young autistic children
b. mtDNA acts as an innate pathogen → leads to auto-inflammation
2.
Corticotropin-releasing hormone (CRH) stimulates mast cells
under conditions of stress
a. Cytokines increase vascular permeability → disrupts blood–brain barrier
b. Neurotoxic molecules enter the brain → leads to brain inflammation
Perinatal Stress and Autism
Perinatal = weeks immediately before or after birth
NT and CRH are secreted in response to stress
Increased CRH in serum of mothers → high anxiety
levels near end of gestation
NT and CRH trigger mast cell activation
→ Currently, no definitive pathogenesis of autism
Clinical Methods to Treat Autism
Behavioral
Early intensive behavioral
intervention improves
learning, communication and
social skills in young children
with autism
Medical
Many people with autism have
additional medical conditions on
top of their neurological
impairment and when properly
treated their attention, learning
and behavior have improved
*Each child or adult with autism is unique and, so, each autism*
intervention plan should be tailored to address specific needs
Spectrum of Symptoms
* 1.8 times more likely to have asthma,
* 1.6 times more likely to have eczema or skin allergies,
* 1.8 times more likely to have food allergies,
* 2.2 times more likely to have chronic severe headaches, and
* 3.5 times more likely to have chronic diarrhea or colitis (inflammation of the
colon)
The three core symptoms are sleep disturbance,
seizures and gastrointestinal (GI) distress
Pharmacological Treatment
Most medicines prescribed are “off label” medications, meaning
that their FDA approval is for another treatment
SSRIs
Ease social difficulties (eg: fluoxetine)
Antipsychotic
.
Treat symptoms of irritability and the core symptoms
(eg: risperidone, aripiprazole)
Anticonvulsants
Reduce the amount of seizures (eg: Tegretol)
Stimulants
Treat hyperactivity (eg: Ritalin)
Novel Methods
Naturally occurring flavonoids can inhibit human mast cell release
of inflammatory molecules
Quercetin prevents stress induced autistic behavior
Luteolin inhibits maternal interleukin-6-induced autistic behavior in social interactions
NeuroProtek reduces blood brain barrier disruption and brain inflammation
Summary Slide
Autism is a complex disorder
gene susceptibility can increase risk of developing autism
Genetic Susceptibility
PTEN and TSC1/2 gene mutations lead to hyperactive mTOR signalling = over-activation and proliferation of mast
cells
Mast cells could play a role in the disorder
pro-inflammatory molecules like IL-12, IL-6, IFNg, TNF are increased
allergic response during pregnancy are correlated with ASD
Non-immune mast cell triggers include CRH and NT
Increased vascular permeability disrupts BBB, which results in brain inflammation
NT releases mtDNA which causes autoinflammatory response
Perinatal stress may increase CRH levels; possible pathogenesis
Naturally occurring flavonoids can inhibit human mast cell release of inflammatory molecules
Quercetin and Luteolin
References
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Croen, L. A. et al. (2005). Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/15699309
da Silva, E. Z. M. et al. (2014). Mast Cell Function: A New Vision of an Old Cell. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230976
Geschwind, D. H. (2008). Autism: Many Genes, Common Pathways? Retrieved from http://www.sciencedirect.com/science/article/pii/S009286740801307X
Moon, T. C. et al. (2014). Mast Cell Mediators: Their Differential Release and the Secretory Pathways Involved. Retrieved from
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4231949/
Newschaffer, C. J. (2007). The Epidemiology of Autism Spectrum Disorders. Retrieved from
http://www.annualreviews.org/doi/abs/10.1146/annurev.publhealth.28.021406.144007
Palmieri, L. & Persico, A. M. (2010). Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/20441769
Vos, T. et al. (2015). Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries,
1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Retrieved from http://www.sciencedirect.com/science/article/pii/S0140673615606924
Theoharides, T. C. (2012). Mast cell activation and autism. Retrieved from http://www.sciencedirect.com/science/article/pii/S0925443910002954
Theoharides, T. C. (2013). Focal brain inflammation and autism. Journal of Neuroinflammation. Retrieved http://www.ncbi.nlm.nih.gov/pubmed/23570274
Theoharides, T. C. et al. (2013). The "missing link" in autoimmunity and autism: extracellular mitochondrial components secreted from activated live mast cells. Retrieved
from http://www.ncbi.nlm.nih.gov/pubmed/23831684
Zhang, B. et al. (2012). Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/23284625