Autism and Mast Cells

Spencer Martin, Peter Gao, Chris Chiu and Faizan Baig

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: 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 understoodhttp://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 Medical

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

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 TreatmentMost 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 SlideAutism 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

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