This blog is a way of sharing the information and resources that have helped me to recover my son Roo from an Autism Spectrum Disorder. What I have learned is to view our symptoms as the results of underlying biological cause, which can be identified and healed. I say "our symptoms" because I also have a neuro-immune disorder called Myalgic Encephalomyelitis.

And, of course, I am not a doctor (although I have been known to impersonate one while doing imaginative play with my son)- this is just our story and information that has been helpful or interesting to us. I hope it is helpful and interesting to you!

Tuesday, May 17, 2016

Mast Cell Activation in the Brain and Neurological Disorders (especially autism)

This talk given by Dr Theoharides sponsored by The Autism Research Institute provides similar information to another interview with him that I have already published my notes for here, however this talk provides much more information and depth.  You may want to start with the other interview if this is new or overwhelming to you.  Here is more about Dr Theo (as he is affectionately called in the mast cell disease world) from the blurb for the talk "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."  So basically, he is NOT some "fringe" quack but rather an accomplished and well respected doctor and researcher whose groundbreaking work is changing the way that autism (among many other things) is understood within mainstream medicine.


His central premise in this presentation is that autism, or at least a subset of cases of autism, is essentially an "allergy of the brain".  He tells us what allergies are, what causes them, why there could be an association with autism, and maybe even what we can do about it.  One of the cornerstone beliefs in western medicine has been that the brain does not "get" allergies.  However, many people with allergies do get neurological symptoms such as feeling irritable, having difficulty concentrating, even movement disorders such as tics following an exposure to an allergen.  The diencephalon is the part of the brain that "receives sensory stimuli and then sends them out to other parts of the brain, and then regulates the emotions that we generate against those sensory stimuli- and what do you know, most autistic children have behavior problems that relate to exactly that."  What prompted him to make the connection between autism and brain allergy is that the diencephalon has a high number of mast cells, which are immune cells that are at the center of allergic reactions..yet the brain doesn't get allergies?  Why would a cell that is thought to only be involved in allergic reactions be so plentiful in such an important region of the brain, when supposedly the brain doesn't get allergies?

First, we need to understand what allergies are.  "True" allergies occur when a specific thing that we are allergic to (an antigen) causes our bodies to produce IgE (immunoglobulin E), which then triggers the mast cells to react by degranulating, which means releasing large amounts of preformed mediators that were stored inside the cell.  Many children with autism appear to be allergic, meaning that they show symptoms that look like allergy, but do not test positive for allergies when tested using skin prick testing or RAST testing (looking for IgE in the blood).  He says that due to this many families with autistic children are sent home from the allergist's office being told that "it's all in their heads" when he emphatically states that this is NOT true- this is real.  Recently a new allergic disease has been identified called Mast Cell Activation Syndrome (MCAS) that explains this- a person with MCAS can have any or all of the symptoms of allergy but have no positive allergy testing at all.  One of the significant things about MCAS is that it is the first time that an allergic disease has neurological symptoms as part of it's description.

Mast cells were discovered in 1887 by Dr Paul Ehrlich.  He had no idea what the cells did- he thought they were feeding something because of the little granules inside of them.  About the same time, the term "anaphylaxis" was coined when two French researchers were doing experiments in which they injected dogs with ground up jellyfish tentacles in the hopes of causing immunity to the toxin.  They intended to call this effect "prophylaxis" which means "to protect", but when the dogs were re-injected with the toxin, rather than being protected as expected, they died.  The cause of death was then called "anaphylaxis" because the treatment had had the opposite effect.

An allergic reaction is when a mast cell is triggered by IgE and an antigen, which causes it to degranulate (or as he says) basically explode like a hand grenade.  Mast cells contain around 500 granules, which rupture and release their contents when triggered, which includes more than 50 chemicals.  We only have medicines to counter one of these chemicals, histamine, however he thinks that it's the other molecules that are more strongly associated with autism.  His lab was the first to show that mast cells could also release chemicals selectively, that is *without* degranulating (rupturing open), including chemicals that "can cause allergic-like reactions, inflammation, and sensitize neurons and cause neuronal damage" (when cells "leak" their contents in this way it will not show up on a biopsy the way a degranulated cell would).

In addition to IgE, other mast cell triggers include some components of the compliment system (associated with blood clotting, so anything that triggers clotting in the blood can trigger the mast cell), toxins released from bacteria and viruses, and more.  Other chemicals released from mast cells (called mediators) include leukotrienes (involved in asthma), cytokines, chemokines, TNF (tumor necrosis factor, which is a major player in Rheumatoid Arthritis), and more.  Interestingly, even in the same sample not all of the mast cells will react to the same what causes this heterogeneous response?  If we can figure out why some cells are not reacting it may lead to treatment options.

Mast cells also have a wide repertoire of molecules used for communication with other cells in the immune system, as well as pathogens including bacteria, viruses, parasites, and fungi.  Mast cells actually orchestrate the immune response to an immune trigger (an allergy is when the mast cell reacts to an otherwise harmless substance as if it were an invading pathogen).  Mast cells are associated with many other diseases including Multiple Chemical Sensitivities, Chronic Fatigue Syndrome, Fibromylagia, Interstitial Cystitis, and more.  He notes that these disorders are all relatively newly recognized and are increasing along with autism, further evidence that they may share physiology.  He also makes the point that we are also having an epidemic of asthma, despite better treatments, better knowledge, better air filters, and better vacuum cleaners.  So clearly something has been going on recently to drive an increase in allergic diseases.  Why are all of these diseases getting worse?  Do they share a commonality?

He believes the mast cell is the "canary in the coalmine" of the body.  Mast cells have existed phylogenetically (in all species) from long before we had a brain or an immune system.  They must have an important role in sensing the environment in order to be maintained by evolution so strongly.  They are also all over the body- in the gut, the skin, our eyes, our tongue, and of course in our brain (around 15:00 he discusses how mast cells in the brain activate cells differently than in the rest of the body).  He believes that they are there to sense danger and to help the body respond.  The recent rise in allergic (and inflammatory) diseases indicates that something has changed- either the mast cells are over-reacting to stimuli because they are somehow lacking what they need to function properly, and/or because they are being bombarded with too many stimuli to respond appropriately to each one.

His lab tested to see if mercury can stimulate mast cells and found that yes, mercury induces inflammatory mediator release from human mast cells.  He makes the point that mercury is in many things in addition to vaccines (and yes it is still in some), it is also in fish and some pesticides, for example.  They also found that if the mast cells were exposed to both mercury and another chemical released from nerve cells during stress the toxic effect is synergistic (the mast cells release even more mediators).  It's possible then that brain allergy results from more than one toxin, it may be the result of a combination of toxins that have a synergistic effect.

Are there mast cells in the brain?  Mast cells: the immune gate to the brain.  Mast cells are a critical part of the blood brain barrier.  They can be seen wrapped around blood vessels in the brain, with the job of protecting our brains from the toxins that might have made it into our bloodstreams.  Mast cells, along with red blood cells and endothelial cells, regulate the blood-brain-barrier (BBB).  Mast cells in the brain don't get triggered by allergens, they get triggered by other things.  Research also shows that mast cells are the most numerous in the brain during very early development.  So not only are they the most concentrated in the part of the brain very likely to be central to autism symptomatology, but they are also the most numerous at the time that autism sets in.  Also, mast cells are so close to nerves- sometimes even wrapped around them- that when they release their contents it can't but effect the nerves and damage them.

Most mast cell granules contain the enzyme tryptase which acts as a meat tenderizer.  If tryptase is released onto a neuron he believes that it kills the neuron, and that this is part of what is happening in the diencephalon in autism.  This is why he calls it a "focal brain allergy", because the reaction is not happening throughout the brain, but rather in those areas that are particularly important for social behavior and language.  It's known that many kids with autism do not do well with stress, and it has also been observed in the evidence that children born to mothers who were very stressed during pregnancy are more likely to have children with autism.  CRH is the first hormone in the brain released when we are under stress (it is what triggers the fight/flight response) and his lab found that mast cells are located near the neurons that release this hormone.  They found that the extreme states of stress that people with autism can get into can and do trigger mast cells to react.

From this point on in the presentation he presents many research articles, some from his lab and some done by other researchers.  These include:

Mast cells and inflammation
This paper establishes that mast cells drive inflammation, which he describes as the extreme form of allergy.  

Corticotropin-Releasing Hormone and Brain Mast Cells Regulate Blood-Brain-Barrier Permeability Induced by Acute Stress
A lot of children with autism have symptoms including food allergies, food intolerances, skin eruptions, brain fog, elevated levels of certain markers of brain inflammation (such as IL6 and TNF), intolerance of stress, lack of eye contact, loss of speech, reduced social engagement, and mitochondrial dysfunction.

Autism spectrum disorders: concurrent clinical disorders.
Found a high degree of correlation between eczema and autism and ADHD.

Cognitive function of 6-year old children exposed to mold-contaminated homes in early postnatal period. Prospective birth cohort study in Poland.
Found that children who were allergic to mold from these exposures had a lot of trouble with cognitive function.  In the US these kids would be called autistic.  Mold is not a typical allergen but it does stimulate mast cells.  

He says "So we're talking about environmental toxins, we're talking about mercury, we're talking about mold, we're talking about stress, put them all together, now we're having a crisis."

So he pulled all of this together and wrote a review...
Mast cell activation and autism

Research has shown that in mice acute stress (being confined in a small space) causes the BBB to open up after just 30 minutes of stress.  In genetically altered mice that do not have mast cells there is no breakdown of the BBB from stress.  Both types of mice released the same amount of cortisol from the stress so that wasn't the factor.  There is also direct evidence because they have found receptors on the surface of mast cells for the CRH.
Mast cells as targets of corticotropin-releasing factor and related peptides.

Mast cells also line the gut-blood barrier.  They are also in the Broca area that regulates language.  

He then goes on the hypothesize a fascinating connection between mast cell activation and mitochondrial dysfunction, which is another common finding in people with autism.  Mitochondria used to be bacteria WAY in the past but evolved to live synergistically with our own cells.  If they are to be destroyed they are destroyed in the cell by autophagy, they do not leave the cell.  He hypothesizes that if mitochondria or their components leave the cell the body will mistake them as an infection and will mount a massive immune inflammatory response.  So in autism not only is there the allergic-like symptoms, but also a mistaken "pathogen-fighting" response.  I wonder if this could be why MCAS and PANDAS can look so much alike?

Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: relevance to atopic dermatitis.
This research showed that mitochondria can move.  Once the mast cell is activated the mitochondria move to the cell surface.  The mito also broke down into smaller pieces. 

Stimulated Human Mast Cells Secrete Mitochondrial Components That Have Autocrine and Paracrine Inflammatory Actions
The little mitochondria are released outside the cell when mast cells are triggered.  

Mitochondrial DNA is very different than genomic DNA.  Extracellular mitochondrial components cause neutrophils and mast cells to release inflammatory mediators (IL5?), and cause neurons to die.  

Mitochondrial DNA Toxicity in Forebrain Neurons Causes Apoptosis, Neurodegeneration, and Impaired Behavior 

He found that the level of mito DNA in the serum of autistic children is highly elevated.  

Extracellular Mitochondrial Components Secreted from Activated Live Mast Cells Act as “Innate Pathogens” and Contribute to Autism Pathogenesis

Microglia and mast cells: two tracks on the road to neuroinflammation.
Mast cells work together with the microglia, the brain's primary immune cells.

Abnormal microglial-neuronal spatial organization in the dorsolateral prefrontal cortex in autism.

Most common genetic finding in autism has to do with a molecule called PTEN, which regulates another molecule called mTOR.  (from SnapShot: Genetics of Autism)  (I will update this post to include more information on this topic)

Activation and function of the mTORC1 pathway in mast cells.
mTOR has a high association with autism, so the genes most associated with autism are also governing mast cells.  mTOR means "mammalian target of rapamycin" which was an old antibiotic.  Rapamucin blocks mTOR.  Luteolin is an even more potent blocker of mTOR.  

PTEN deficiency in mast cells causes a mastocytosis-like proliferative disease that heightens allergic responses and vascular permeability.

Luteolin is a mast cell inhibitor.

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1.

Luteolin protects dopaminergic neurons from inflammation-induced injury through inhibition of microglial activation.

Flavonoids, a prenatal prophylaxis via targeting JAK2/STAT3 signaling to oppose IL-6/MIA associated autism.Focal brain inflammation and autism.

Focal brain inflammation and autism.