Autism Breakthroughs

A breakthrough in diagnosing autism is occurring and not just diagnosing autism but a medical condition resulting in autism. The implications of this are wide ranging and could change how autism is viewed and treated by medical professionals.

 

Doctors at major universities are researching an autoimmune condition that is the medical cause of autism (1, 2). There is a growing body of peer reviewed medical research that consistently points to one part of the immune system and can even identify subtypes.

 

A Blood Test for Autism

One doctor has found a way to diagnose (3) this condition with a simple blood test and can even identify subtypes of autism, children with and without intestinal symptoms. This opens the door to amazing possibilities in detecting, treating, and even preventing autism. This test can be done at any age could tell a doctor a child is developing autism or is about to. An added benefit is that a child could have a medical diagnosis code for the doctors and for insurance companies along with the beginnings of a treatment plan. No longer would doctors be able to say “It’s just Autism

 

New Proven Treatments

New treatments are being tested now and the possibility of a new prescription specifically to prevent, and even reverse, autism is looking to be a real possibility. Clinical trials on current available treatments are showing significant reduction of symptoms to over 60% of children with autism. One clinical trial has shown that this treatment allows children with autism to developmentally catch up to their neurotypical peers. This is far better than any other available treatment. More research is needed to bring these improved treatments to the general medical establishment and as the US Government, through the NIH, hardly ever funds research into the medical side of autism it is up to the public to fund these efforts.

 

Triggered by Environmental Toxins

This autoimmune condition starts when a child's body gets overloaded with environmental toxins (4), anything from metals to PBCs. This can be exasperated when there is an infection, virus and or even extreme stress. Every child has a set tolerance to these “toxins” and when that level is reached a part of the immune system, the mast cell, is triggered. In certain conditions that are present in infants and toddlers a chain reaction in the immune system can start that leads to an autoimmune type condition called a Brain Immunity Storm.

 

Immune System Controlled by Mast Cells
Relatively recent research has proved these mast cells act as the orchestra conductor of immune reactions as they control reactions from allergies to inflammation, and a wide range of other immune regulation functions. Their effect is wide ranging from directing attacks on viruses and bacteria to intestinal movement (5) and gut bacteria (6, 7) to adrenal (8) and pituitary function.


If mast cells get overwhelmed they can be activated and “degranulate" (think explode). When mast cells degranulate they release all their immune molecules at once. This is needed for a major immune response like a traumatic injury, but this reaction is not supposed to spread too far. Children are born with a high amount of mast cells in their brain making their immune systems very sensitive, there are so many mast cells that degranulation can start a chain reaction in the immune systems that leads to a Brain Immunity Storm.

 

An Immune Chain Reaction

Once this chain reaction starts the first symptoms are usually gut issues and rashes. These are often accompanied by an initial high fever. As the mast cell chain reaction spreads it can lead to the protective gut blood and blood brain barriers being broken down (9). The blood brain barrier is in place around your brain to keep out almost anything besides simple sugar molecules. Once the blood brain barrier is broken down the mast cells in the brain get activated along with the immune system of the brain, the microglia cells. The microglia cells start to react with the mast cells in the brain and this is what leads to Autism Spectrum Disorders. This interaction between the mast cells and the microglia is called a Brain immune Storm.
 

A Recent Discovery
If you ask why this mast cell to microglia cell activation and interaction has not been found before it is mainly because this part of the immune system has been poorly understood until more recently. Mast cells have been associated with allergies for a long time, only more recently have they been better understood to be a conductor of the immune system. In the footnotes it can be seen that most research has only occurred in the last few years. In fact almost all doctors will not even know these calls do anything besides trigger allergic response. 

 

 

Blood Brain Barrier and Brain Inflammation

In the brain mast cells are the gatekeepers of the protective barrier that keeps the brain safe and they are often found hugging the blood vessels and next to nerve endings. A regular immune response of the mast cells is to coordinate a response to viruses and bacteria by releasing. If mast cells in the body are triggered in a big enough chain reaction the mast cells around the blood vessels in the brain release molecules that make the protective blood brain barrier permeable (10, 11).


If all this was not bad enough there are other molecules being released in this storm that cause brain inflammation(12), disrupt neurotransmitters(13) (poor brain communications), cause seizure or seizure-like activity, and even trigger aggression and other adrenal responses. The brain's immune system has a safety rule where it is only allowed to work for a short period of time to prevent damage to the brain. In a Brain Immunity Storm the mast cells in the brain have been activated and release certain inflammatory molecules that override this safety rule.


Learning Difficulties from Immune Reaction
Children with autism have difficulty learning especially when they are younger. This looks to be due to a lack of the natural learning molecule, dopamine. In a Brain Immunity Storm one of the molecules released is called neurotensin and it has many effects in the brain. Neurotensin released in great a quantity during a Brain Immunity Storm is toxic to brain cells and causes dopamine levels to drop. This will make learning very difficult to impossible.




Speech, Sensory, and Social Skills disrupted

Neurotensin also affect two regions of the brain more than others, these are the ones responsible for speech (Broca's area), social skills and sensory (Diencephalon). This is due to those areas of the brain having the highest number of mast cells and the most receptors for neurotensin(17). The effect on the Diencephalon is where most “autistic-like” behaviors come from as parts of the diencephalon work closely with the adrenal gland to control moods, emotions, aggression, fight or flight response, pain responses and more.


Explains the role of genetics

An abundance of research has been done on Autism and Genetics finding hundreds of genes that show an increased risk of autism, but none (0) that cause autism. Some of the genes associated with autism are also known to be related to making the immune system easier to activate. These genes set the threshold of how easy it is to activate mast cells, but the genes do not cause mast cells to be activated. This explains how autism is more prevalent in some families and yet there is not genetic cause, as a decade of genetic research into autism has shown.

 

Mitochondrial Dysfunction

Mitochondria are the power generators for cells in our bodies. Mitochondria dysfunction, seen as low energy production, is often seen in autism, but rarely is a true mitochondria disorder found. This points to some other medical condition disturbing the mitochondria and may have a lot to do with the mast cell. When mast cells degranulate they release their mitochondrial content. This is unique to mast cells as no other cell has ever been found to do this. This should also never happen because is mitochondria are released from a cell the immune system attacks them thinking the mitochondria are a bacterial infection. Due to this a release of mitochondria into the bloodstream will look like mitochondrial dysfunction to some blood tests. These mitochondrial components cause massive oxidative stress along with making the immune response even worse.


Why Autism only Starts in Children
The effects of autism start only in young children, under 3. The reason Autism does not start after that age brings us back to the mast cell. When we are born we have a huge number of mast cells in our brains making our immune system very sensitive. During the first few years of life the number of mast cells in the brain drops quickly.


Research Breakthroughs

The research is new but progress is being made with a new blood test for diagnosis under development and a possible new prescription is being investigated. Currently the best therapies are supplements found to "calm" this Immune reaction, the Brain Immunity Storm. One of these supplements has been shown to be highly effective in multiple independent clinical trials. (15, 16)  One clinical trial even shows that children with autism taking the supplement NeuroProtek, made by Algonot, developmentally catch up to their neuro-typical peers. As good as these results are there is a new compound that may become a drug being researched with animal trials showing an amazing improvement, but that would be a prescription and drug development takes a lot of time and a lot of money.

 

Much more research is needed before there is an approved blood test and even better treatments and several organizations, including AutismFreeBrain, are working as best we can to get to this goal as fast as possible even in the absence of government funding.



References
  1. T.C. Theoharides et al. The "missing link" between autoimmunity and autism. Autoimmunity Review 2013 http://www.autismfreebrain.org/sites/default/files/research/pdf/the_missing_link_in_autoimmunity_and_autism_autoimm_rev_2013.pdf

  2. T. Theoharides, et al, Mast cell activation and autism, Biochimica et Biophycica Acta 2012 http://www.autismfreebrain.org/sites/default/files/research/pdf/autism_mast_cells_bba_2012.pdf

  3. I Tsilioni, et al. Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism. Translation Psychiatry 2014 http://www.nature.com/tp/journal/v4/n10/pdf/tp2014106a.pdf

  4. Duraisamy Kempuraj et al. Mercury induces inflammatory mediator release from human mast cells. Journal of NeuroInflammation 2010 http://www.autismfreebrain.org/sites/default/files/research/pdf/autism_mercury_mast_cells_j_neuroinfl_2010.pdf

  5. DeWinter et. al., Intestinal mast cell in gut inflammation and mobility disturbances, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2012 http://www.sciencedirect.com/science/article/pii/S0925443911000718

  6. Heitman, The Role of Mast Cells in the Defence against Pathogens, PLOS Pathogens, 2012 http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1002619

  7. Pathl, The Role of Mast Cells in Bacterial Enteritis, The American Journal of Pathology, 2007 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1934547/

  8. Matsumoto, et.al., Brain Mast Cells Act as an Immune Gate to the Hypothalamic-Pituitary-adrenal Axis in Dogs, Journal of Experimental Medicine, 2001, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193441/

  9. T.C. Theoharides, B. Zhang. Neuro-inflammation, blood-brain barrier, seizures and autism. . Journal of NeuroInflammation 2011 http://www.autismfreebrain.org/sites/default/files/research/pdf/autism_seizures_jni_2012.pdf

  10. T.C. Theoharides, Mast Cells: The Immune Gate to the Brain. Life Sciences, 1990 http://www.mastcellmaster.com/documents/brain-health/Life-Sciences-1990-Mast-Cells-The-Immune-Gate-to-the-Brain.pdf

  11. P. Esposito, et al Corticotropin-Releasing Hormone and Brain Mast Cells Regulate Blood-Brain-Barrier Permeability Induced by Acute Stress. Journal of Pharmacology and Experimental Therapeutics 2002 http://www.autismfreebrain.org/sites/default/files/research/pdf/crhbrain_mast_cellsbbb.pdf

  12. T.C. Theoharides, B. Zhang. Neuro-inflammation, blood-brain barrier, seizures and autism. Journal of Neuroinflammation. 2011 http://www.autismfreebrain.org/sites/default/files/research/pdf/autism_seizures_jni_2012.pdf

  13. A. Ghanizadeh. Targeting Neurotensin as a Potential Novel Approach for the Treatment of Autism. Journal of Neuroinflammation. 2011. http://www.medscape.com/viewarticle/730438

  14. D Kempuraj. et al. Luteolin inhibits myelin basic protein-induced human mast cell activation and mast cell-dependent stimulation of Jurkat T Cells. British Journal of Pharmacology 2008 http://www.autismfreebrain.org/sites/default/files/research/pdf/luteolin_t_cells_mast_cells_bjp_2008.pdf

  15. A. Taliou, et al. An Open-Label Pilot Study of a Formulation Containing the Anti-Inflammatory Flavonoid Luteolin and Its Effects on Behavior in Children With Autism Spectrum Disorders. Clinical Therapeutics 2013 http://www.autismfreebrain.org/sites/default/files/research/pdf/autism_neuroprotek_clin_therapeutics_may_2013.pdf

  16. T.C. Theoharides, et al. A Case Series of a Luteolin Formulation (NeuroProtek) in children with Autism Spectrum Disorders. International Journal of Immunopathology and Pharmacology. 2012 http://www.mastcellmaster.com/documents/NeuroProtek-IJIP6-2012.pdf

  17. T.C. Theoharides, Is Subtype of Autism an Allergy of the Brain, Clinical Therapeutics, 2013 http://www.autismfreebrain.org/sites/default/files/research/pdf/autism_subtype_brain_allergy_clin_therapeutics_may_2013.pdf

 

 

 

Additional research on Mast cells and the Adrenal, pituitary, and hypothalamus 

Research dating back as far as 1935 shows that mast cells are an integral player in many behavioral actions and psychology and many of these are directly related to autism such as

  • aggression & fight/flight – Adrenal gland

  • thyroid, temperature regulation, stress, growth, pain response - Pituitary gland

  • anxiety behavior and physiology may be mediated through mast cell contribution of serotonin to the hippocampus, a brain region where many mast cells reside  

  • Improved behavior during fevers – hypothalamus

 

Adrenal mast cells modulate vascular and secretory responses in the intact adrenal gland of rats

http://joe.endocrinology-journals.org/content/121/2/253.abstract

 

Mast Cells of the Pituitary Gland – Research dating back to 1935

http://www.nature.com/nature/journal/v205/n4978/abs/2051334a0.html

 

Mast Cells effect brain physiology and behavior – 207 Pages

http://academiccommons.columbia.edu/catalog/ac:131582

 

Neurotensin, dopamine, and sleep issues. 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369230/0

 

Serotonin of Mast Cell origin contributes to hippocampal function

http://www.ncbi.nlm.nih.gov/m/pubmed/22632453/

Serotonergic deafferentation of the hippocampus through ablation of serotonergic neurons results in a 60-80% decrease in serotonin in the hippocampus (Altman et al., 1990), suggesting that as much as 20-40% of serotonin may originate from mast cells.  

Upon application of a mast cell degranulating agent, serotonin levels within hippocampi of control mice with mast cells were ~50% higher  

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