Also see post Mast Cells, MCAS, and Psychiatric Symptoms and Neuroinflammation
Mast Cells, Stress, Fear and Autism Spectrum Disorder
“Prenatal stress has been associated with higher risk of developing ASD
in the offspring. Moreover, children with ASD cannot handle anxiety and respond
disproportionately even to otherwise benign triggers. Stress and environmental
stimuli trigger the unique immune cells, mast cells, which could then trigger
microglia leading to abnormal synaptic pruning and dysfunctional neuronal
connectivity. This process could alter the “fear threshold” in the amygdala and
lead to an exaggerated “fight-or-flight” reaction. The combination of
corticotropin-releasing hormone (CRH), secreted under stress, together with
environmental stimuli could be major contributors to the pathogenesis of ASD.
Recognizing these associations and preventing stimulation of mast cells and/or
microglia could greatly benefit ASD patients.”
Mast cell activation and autism
Focal brain inflammation and autism
"Many children with ASD regress at about age 3 years, often after a
specific event such as reaction to vaccination, infection, stress or
trauma implying some epigenetic triggers, and may constitute a distinct
phenotype. ASD children respond disproportionally to stress and are also
affected by food and skin allergies. Corticotropin-releasing hormone
(CRH) is secreted under stress and together with neurotensin (NT)
stimulates mast cells and microglia resulting in focal brain
inflammation and neurotoxicity. NT is significantly increased in serum
of ASD children along with mitochondrial DNA (mtDNA). NT stimulates mast
cell secretion of mtDNA that is misconstrued as an innate pathogen
triggering an auto-inflammatory response. The phosphatase and tensin
homolog (PTEN) gene mutation, associated with the higher risk of ASD,
which leads to hyper-active mammalian target of rapamycin (mTOR)
signalling that is crucial for cellular homeostasis. CRH, NT and
environmental triggers could hyperstimulate the already activated mTOR,
as well as stimulate mast cell and microglia activation and
proliferation. The natural flavonoid luteolin inhibits mTOR, mast cells
and microglia and could have a significant benefit in ASD."
Is a subtype of autism an allergy of the brain?
"Activation of brain mast cells by allergic, environmental, immune,
neurohormonal, stress, and toxic triggers, especially in those areas
associated with behavior and language, lead to focal brain allergies and
subsequent focal encephalitis. This possibility is more likely in the
subgroup of patients with ASD susceptibility genes that also involve
mast cell activation."
An integrated transcriptomic analysis of autism spectrum disorder
"Functional enrichment analysis demonstrated that differential expressed
genes were significantly enriched in inflammation/immune response,
mitochondrion-related function and oxidative phosphorylation.
Interestingly, genes enriched in inflammation/immune response were
up-regulated in the brain tissues and down-regulated in the blood."
Autism is Associated with Increased Allergies and Atopic Disease (Mast Cell Related)
Autism spectrum disorders: concurrent clinical disorders.
Found an association between autism and food allergies.
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.
Notes:
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 stimulus...so 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.
Mast cells as targets of corticotropin-releasing factor and related peptides.
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?
