1. Autism and Mast Cells Spencer Martin, Peter Gao, Chris Chiu and Faizan Baig PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. 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

3. 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

4. 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

5. Mast Cells and Autism

6. 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

7. 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

8. 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

9. 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

10. Clinical Methods to Treat Autism BehavioralMedical Early intensive behavioral intervention improves learning, communication and social skills in young children with autism 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

11. 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

12. 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)

13. 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

14. 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

15. References -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 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 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 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 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 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 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 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 http://www.ncbi.nlm.nih.gov/pubmed/23284625