Is ME/CFS caused by MCA? A comparison of ME/CFS Comorbid diagnoses against MCA

[Lasse]

Mast Cell Activation (MCA) from Mast Cells appears to be able to cause all symptoms, triggers in ME/CFS.
Those with ME/CFS often have many comorbidities that are overrepresented in those with ME/CFS.
Below I look at these comorbid diagnoses and their connection to Mast Cells and Mast Cell Activation (MCA).

What do you think, can ME/CFS have a cause in Mast Cell Activation (MCA)?
Are there any comorbid diagnoses I have forgotten?

Comorbid diagnoses in those with ME/CFS.

ME/CFS Allergy:
Allergies also tend to be more common in people who have ME/CFS than in the general population. Many people with ME/CFS have a history of allergies years before the onset of the syndrome. Sometimes they report a worsening of allergic symptoms or the onset of new allergies after becoming ill with ME/CFS.

Source:
• Chronic Fatigue Syndrome Suzanne D. Vernon, PhD Conditions & Treatments

Scientific articles:
• Allergy and the chronic fatigue syndrome

Mast Cell allergy:
When a person who is allergic to a particular allergen comes into contact with it, an allergic reaction occurs:

• When the allergen (such as pollen) enters the body, it triggers an antibody response.
• The antibodies attach themselves to mast cells, which respond by releasing histamine.
• When the release of histamine is due to an allergen, the resulting inflammation is irritating and uncomfortable.

Kilde:
• What is Allergy?

ME/CFS Asthma:
Asthma was also more common in the CFS/ME group (17.5%) than in the two control groups (11% in both groups).

Source pdf on ResearchGate:
• Comorbidities treated in primary care in children with chronic fatigue syndrome myalgic encephalomyelitis A nationwide registry linkage study from Norway

Mast Cell Asthma:
Mast cells and their mediators have been implicated in the pathogenesis of asthma and allergy for decades.

Source:
• Mast Cells and Their Progenitors in Allergic Asthma

ME/CFS IBS:
Katrina Berne reports a prevalence of 50-90% for IBS symptoms (including diarrhoea, nausea, gas, and abdominal pain) in ME/CFS patients.

Source:
• Irritable bowel syndrome ME Pedia

Mast cell IBS:
Agents that produce IBS symptoms such as foods and stress can activate mast cells, which then secrete mediators. These mediators such as histamine and protease have been reported to induce hypersensitivity in the nerve terminals of pain-transmitting afferent neurons. Source:

Source:
• The Role of Mast Cells in Irritable Bowel Syndrome

Scientific articles:
• Mast Cell Regulation and Irritable Bowel Syndrome: Effects of Food Components with Potential Nutraceutical Use
• Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside
• The Emerging Role of Mast Cells in Irritable Bowel Syndrome
• The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome

ME/CFS fibromyalgia:
The most common overlapping condition with ME/CFS is fibromyalgia. While some have posited ME/CFS and FM are variants of the same illness. MD summoned considerable amounts of data that suggest the two illnesses differ with different pathophysiological processes leading to different treatments.

Source:
• https://me-pedia.org/wiki/Fibromyalgia

Mast cells fibromyalgia:
Our findings indicate that mast cells contribute to the development and maintenance of painful symptoms observed in the experimental fibromyalgia

Source:
• Involvement of peripheral mast cells in a fibromyalgia model in mice

Scientific articles:
• Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome

ME/CFS hEDS:
A Swedish study of 234 ME/CFS patients meeting the Canadian Consensus Criteria found that 49% of patients had hypermobility and 20% met the criteria for hEDS.

Source:
• https://me-pedia.org/wiki/Ehlers-Danlos_syndrome

Mast Cels hEDS:
The most common form, hypermobile type EDS (hEDS) and its variant, hypermobile spectrum disorder (HSD), are correlated with rheumatologic and inflammatory conditions. Evidence is still needed to determine the pathophysiology of hEDS; however, the association among these conditions and their prevalence in hEDS/HSD may be explained through consideration of persistent chronic inflammation contributing to a disruption of the connective tissue. Aberrant mast cell activation has been shown to play a role in disruption of connective tissue integrity through activity of its mediators including histamine and tryptase which affects multiple organ systems resulting in mast cell activation disorders (MCAD).

Source:
• Association of mast-cell-related conditions with hypermobile syndromes: a review of the literature

Scientific articles:
• Mechanobiology in the Comorbidities of Ehlers Danlos Syndrome
• The relationship between mast cell activation syndrome, postural tachycardia syndrome, and Ehlers-Danlos syndrome

ME/CFS Endometriosis:
Several studies, though, have found higher-than-normal rates of gynecological diseases in ME/CFS. Indeed, they suggest that as many as a third of all women with ME/CFS may suffer from endometriosis and resulting comorbidities.

Source:
• https://www.healthrising.org/blog/2...disorders-klaus-wirths-blood-vessel-diseases/

Mast cells Endometriosis:
Our data show promising evidence that mast cells, under influence of estrogen, are recruited to the endometriotic lesion microenvironment and have an active role in endometriosis pathophysiology.

Source:
• Estrogen mediates inflammatory role of mast cells in endometriosis pathophysiology

Scientific articles:
• NLRP3 Inflammasome Activation of Mast Cells by Estrogen via the Nuclear-Initiated Signaling Pathway Contributes to the Development of Endometriosis
• Mast Cell Activation Syndrome and Endometriosis: A Potential Link for Unexplained Symptoms in Women
• Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis

ME/CFS POTS:
POTS can be a co-morbid condition in ME/CFS patients.
Estimates on the prevalence of POTS among ME/CFS patients varies widely, from 11% to 70%.

Source:
• https://me-pedia.org/wiki/Postural_orthostatic_tachycardia_syndrome

Mast cells POTS:
Patients with MCA disorder may have symptoms suggestive of POTS. However, in these cases one may anticipate that the clinical presentation will be characterized by a broader symptom profile than is the case with typical POTS. In particular, the presence of allergic reactions, gastrointestinal complaints, and to a lesser extent skin disturbances should lead to considering MCA. While no single laboratory finding provides an assured diagnostic marker, the presence of an elevated prostaglandin (prostaglandin D2 and/or F2 alpha), especially in conjunction with an increased second marker such as histamine or less often tryptase, suggests that MCA disorder may be responsible for the POTS‐like symptoms.

Source:
• Mast Cell Activation Disorder and Postural Orthostatic Tachycardia Syndrome: A Clinical Association

ME/CFS ADHD
ADHD in Fibromyalgia and Chronic Fatigue Syndrome Several studies suggest that ADHD may be quite common in fibromyalgia and ME/CFS, and attention problems seem (to me anyway) to be a core feature in these diseases.

Source:
• https://www.healthrising.org/blog/2021/02/05/attention-deficit-fibromyalgia-rheumatoid-arthritis/

Mast cells ADHD
Mast cells may cause ADHD via the following mechanisms: Selective release of inflammatory factors, interacting with glia via CD40L, TLR2/TLR4, histamine receptor, PAR2, CXCR4/CXCL12, complement system, mast cell protease, MAPKs and NF-κB, causing neuronal damage, activating the HPA axis and resulting in BBB breakdown.

Source:
• Mast cell-mediated neuroinflammation may have a role in attention deficit hyperactivity disorder (Review)

Scientific articles:
• An Shen Ding Zhi Ling Alleviates Symptoms of Attention Deficit Hyperactivity Disorder via Anti-Inflammatory Effects in Spontaneous Hypertensive Rats

ME/CFS Multiple Chemical Sensitivity
New chemical sensitivities are recognized as a common symptom of ME/CFS, and some people react to so many substances that they also meet the diagnostic criteria for Multiple Chemical Sensitivity (MCS).

Source:
• https://me-pedia.org/wiki/Chemical_sensitivities

Mast Cell Multiple Chemical Sensitivity
Mast cell activation and mediator release appear capable of explaining the increasingly frequent observations by physicians and their patients of chronic multi-system symptoms and new-onset chemical, food and drug intolerances following exposure to a wide variety of xenobiotics.

Source:
• Chemical Intolerance and Mast Cell Activation: A Suspicious Synchronicity

Scientific articles:
• Mast cell activation may explain many cases of chemical intolerance

ME/CFS interstitial cystitis (IC)
We discuss IC which is a very distressing condition that seems to be more common in people with ME/CFS. It is a poorly understood bladder condition that causes uncomfortable symptoms including pelvic pain.

Source:
• https://meassociation.org.uk/literature/items/interstitial-cystitis-and-me-cfs/

Mast Cell interstitial cystitis (IC)
The mast cell can directly cause vasodilation and bladder mucosa damage while also attracting inflammatory cells, thus causing many of the problems seen in interstitial cystitis. The mast cell appears to be involved in the pathogenesis of interstitial cystitis.

Source:
• The role of the mast cell in interstitial cystitis

Scientific articles:
• Mast cell involvement in interstitial cystitis: a review of human and experimental evidence

ME/CFS Migraines
Migraines are common in people with fibromyalgia and chronic fatigue syndrome. Not only do they occur more frequently, but they tend to be more severe. The cause of migraines in people with fibromyalgia and chronic fatigue syndrome is unknown.

Source:
• https://www.verywellhealth.com/headaches-and-migraines-in-fibromyalgia-and-cfs-716166

Mast Cell Migraines:
Migraine pain is characterized by an intense, throbbing pain in the head area and possesses complex pathological and physiological origins. Among the various factors believed to contribute to migraine are mast cells (MCs), resident tissue immune cells that are closely associated with pain afferents in the meninges.

Source:
• The role of mast cells in migraine pathophysiology

Scientific articles:
• Roles of mast cells and their interactions with the trigeminal nerve in migraine headache
• Shared Fate of Meningeal Mast Cells and Sensory Neurons in Migraine

ME/CFS Mast Cell Temporomandibular joint disorder (TMJ)
Temporomandibular joint disorder (TMJ) causes jaw pain, and people with fibromyalgia (FMS) and chronic fatigue syndrome (CFS or ME/CFS) tend to struggle with TMJ more than those without these conditions.

Source:
• https://www.verywellhealth.com/tmj-in-fibromyalgia-chronic-fatigue-syndrome-716175

Mast Cell Temporomandibular joint disorder (TMJ)
The presence of neuropeptide nerves and mast cells within the TMJ has been shown. Mast cell degranulation products and SP release can contribute to TMJ inflammation.

Source:
• Substance P and mast cells: preliminary histologic analysis of the human temporomandibular joint

ME/CFS & MCAS Small fiber neuropathy (SFN)
Small fiber neuropathy (SFN) associated with ME/CFS and MCAS could decrease the generation of neuropeptides such as Substance P and calcitonin-gene-related peptide (CGRP) released by these nerves. The ensuing deficiency of both vasodilator neuropeptides may contribute to skeletal muscle hypoperfusion.

Source:
• Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?

Scientific articles:
• Mast cell disorders are associated with decreased cerebral blood flow and small fiber neuropathy

 

[Creekside]

No, some similarities does not mean a direct link. I expect that too many of us do not have MCA to claim a direct relationship. MCA does involve immune activation, and immune activation from any cause may trigger or influence ME.

 

[Lasse]

I do not believe that everyone with an ME/CFS diagnosis has an immune disease as there are some who recover on their own.

Mast Cell Activation (MCA) is incredibly difficult to measure. Most of the over 1050 different types of mediators that they can produce and release can also be released by several other immune cells.
All unique mediators except Tryptase have incredibly short half-lives, which makes it incredibly difficult to measure them.

Since you mean Mast Cell Activation (MCA) only has some similarities to what we see in ME/CFS.
Can you then name some of the differences in ME/CFS that do not fit with Mast Cell Activation (MCA)?

ME/CFS and Mast Cell Activation (MCA) have the same symptoms as we see in Long Covid.
• ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature
• Mast cell activation symptoms are prevalent in Long-COVID

From BBC:
'Long Covid triggered our MCAS, but doctors didn't believe us'

From Medscape:
Mast Cell Activation May Underlie 'Chronic Fatigue Syndrome

Investigation of mast cell toll-like receptor 3 in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Systemic Mastocytosis participants using the novel application of autoMACS magnetic separation and flow cytometry

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Metabolic Disease or Disturbed Homeostasis due to Focal Inflammation in the Hypothalamus?

 

[Lasse]

Lecture on brain inflammation and brain fog on YouTube.
From Brain Fog to Mast Cell Activation: Unlocking the Underlying Connections

 

[Baz493]

There are likely to be variations in how CE/ME develop. My own current condition, which hasn't been fully diagnosed yet, involves protracted disrupted GABA receptor function as a result of benzodiazepine withdrawal. However other receptors may be involved. This article details the presence of autoimmune antibodies to G-coupled proteins in some people with ME. https://www.mdpi.com/2077-0383/10/16/3675 As you can see from the next article the microbiome can affect both the levels of G-coupled proteins as well as how they work. So I think it's likely that a long term disrupted microbiome can cause both the mast cell activation which you refer to as well as sufficiently altered G-coupled protein activation that it could induce an autoimmune response from our bodies to try to bring the situation under control.

If I understand the research correctly then it seems that the G coupled receptors are involved in binding and release of guanosine triphosphate in order for synthesis of RNA. That's likely responsible for the RNA alterations in ME. https://pubmed.ncbi.nlm.nih.gov/33184353/ RNA plays roles in pretty much every process in our bodies so it's never healthy when its production gets disrupted.

 

[ruanmalan]

There is probably significant benefit for individuals with either to look into the other -- to help identify and manage some symptoms.
Considering how wide ranging the impact of both of these are I would guess there are a fair amount of people with both ME/CFS and MCAS.
Both are also very diverse and it is hard to accurately generalize about either. There might be types of ME/CFS and types of MCAS that commonly go together and feed into each other.
Chronic, persistent and resident viral infection such as Epstein Barr is an example of something that seems to be able to lead to both ME/CFS and MCAS.
Personally, when my ME/CFS has been at its worst I have had extreme fatigue, exercise intolerance, unrefreshing sleep that one feels worse after, orthostatic intolerance, a sense of lack of oxygen in my brain like I am having mini strokes. It is possible those masked the more typical MCAS symptoms I have for periods now my ME/CFS seems to be better - those are more itchy eyes, runny nose, constricted chest, cough, tight throat

 

[Sarabethn]

Very interesting reading. I have all of the comorbitities listed except IC. And I believe that MCAS played a large part in all of my issues. But I still firmly believe that a viral infection started the whole cascade of symptoms. Very good info!

 

[ChristianBonanno]

Mast Cell Activation may cause all the symptoms of ME/CFS, but what is causing the Mast Cell Activation?

I believe it is high levels of ADP inside the cell and high levels of ATP outside the cell.

You see ADP triggers mast cell de-granulation, so the more ADP the more de-granulation you will have when your body senses an allergen.

P2Y13 receptor is responsible for ADP-mediated degranulation in RBL-2H3 rat mast cells

And high ATP outside the cell also primes MAST cells for de granulation.

Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors

But I think I would better say it is from a high ADP:ATP ratio inside the cell and a low ATP:ADP ratio outside the cell.

This might be a good read for everyone:

P2 receptor-mediated signaling in mast cell biology

And I can see this expressed in the opposite way for myself. I know I have a low of intercellular ATP and I have zero allergies.

 

[Baz493]

This article provides several hypotheses which were being posited back in 2015 regarding the cause of ME. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/ My own condition, which isn't ME or CFS, involves the medication withdrawal kindling and altered GABA signaling which are described as one of the theories. The immune activation which you mention is another of the hypotheses.

 

[ChristianBonanno]

There are likely to be variations in how CE/ME develop. My own current condition, which hasn't been fully diagnosed yet, involves protracted disrupted GABA receptor function as a result of benzodiazepine withdrawal. However other receptors may be involved. This article details the presence of autoimmune antibodies to G-coupled proteins in some people with ME. https://www.mdpi.com/2077-0383/10/16/3675 As you can see from the next article the microbiome can affect both the levels of G-coupled proteins as well as how they work. So I think it's likely that a long term disrupted microbiome can cause both the mast cell activation which you refer to as well as sufficiently altered G-coupled protein activation that it could induce an autoimmune response from our bodies to try to bring the situation under control.

If I understand the research correctly then it seems that the G coupled receptors are involved in binding and release of guanosine triphosphate in order for synthesis of RNA. That's likely responsible for the RNA alterations in ME. https://pubmed.ncbi.nlm.nih.gov/33184353/ RNA plays roles in pretty much every process in our bodies so it's never healthy when its production gets disrupted.

I want to throw a postulation out here for you: What if autoimmune disorders were actually a mechanism the body uses to protect itself?

So lets look at autoimmune antibodies to G-coupled proteins. Why would the body want to get rid of a GPCR? Let's say you over activate the GABA receptor with Benzo. The body sees that this receptor is over activated and so it sends out antibodies to destroy the receptor to stay alive. That makes sense, yes?

No you stop taking Benzo's but this process still goes on for a bit or course, and you get dope sick until the body stops making the antibodies.

Now let's say that people with ME/CFS produce a lot of GABA or just cannot get rid of it (which I believe is the case in many people with ME/CFS). This would over stimulate the GABA receptor just like Benzos. So what is the last resort the body can do? Destroy the GABA receptor with antibodies. Makes sense right?

So in ME/CFS they think the antibodies are bad, but they are not. It is the high GABA in some ME/CFS that is bad and the antibodies are protective.

I think this way of looking at autoimmune diseases will revolutionize treatment for all autoimmune diseases and I am not alone with this line of thought.

But let's look at GABA, GTP, and ATP and why magneiusm is importnat for GABA to work.

When GABA hits the receptor the recpetor looks for GTP inside the cell and uses the energy in GTP to separate the aplha beta subunit. Then the aplha unit will attach to Adenylate cyclase which will then turn ATP into cAMP. The Beta unit will also trigger the VGCC to pull calcium into the cell and the calclum is what triggers the GABA nuron to fire and we feel calm.

So the first thing we know is that if we are low in GTP or ATP then we have no effect when GABA hits the receptor. This will happen if there is a lot of oxdiate stress in the cell. But what is also true is that since Adenylate cyclase needs magnesium to function, if we are low magnesium then GABA will again have no effect on the cell. (This is infact how magneisum help calm people).

The fact that they do not find the GABA GPCR antibodies in all people is becasiue ME is caused by a very individualistic and varying genotype and enviroment. Some people may produce too much GABA and some people might not have enough magnesium fro GABA to work becasue of low ATP.

 

[ChristianBonanno]

This article provides several hypotheses which were being posited back in 2015 regarding the cause of ME. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/ My own condition, which isn't ME or CFS, involves the medication withdrawal kindling and altered GABA signaling which are described as one of the theories. The immune activation which you mention is another of the hypotheses.

You really need to investigate magnesium for your condition:

Magnesium in addiction - a general view - PubMed

Addiction is a dysregulation of brain reward systems that progressively increases, resulting in compulsive drug use and loss of control over drug-taking. Addiction is a brain disease. There is evidence that magnesium deficit is involved in addiction to various addictive substances (heroin...

pubmed.ncbi.nlm.nih.gov

 

[Baz493]

I'm well ahead of you with what you suggest. Doctors tend to hate me because I proved to them that the PL-7 autoimmune antibodies which I have, associated with the disease called myositis, are actually evidence of respiratory failure. The antibodies destroy an enzyme called threonyl-tRNA synthetase, which is produced by cells experiencing hypoxia. You don't have problems with the enzyme unless there are issues with the bodies oxygen supply to cells. When you do the enzyme triggers angiogenesis and, potentially, cancer so destroying the enzyme is a good thing. That ruled out the standard recommended treatment for my condition, lol. Not all autoimmune conditions are a good thing though, as some factors can simply cause a dysregulation of immune function. But I agree with you about the majority of cases.

I have been taking a bunch of supplements for my condition, including magnesium, and my condition has mildly improved. Since learning that a lot of genetic variations, and most diseases, are related to imbalances in the microbiome I have been gradually transitioning to a diet high in prebiotics for healthy bacteria as well as anti-microbial and anti-biofilm substances to help kill off pathogenic bacteria. Since no one has a definitive answer for repairing dysregulated GABA receptors, as occurs in benzodiazepine withdrawal, I am just hoping that rebuilding the microbiome will gradually normalise GABA function.

 

[ChristianBonanno]

The antibodies destroy an enzyme called threonyl-tRNA synthetase, which is produced by cells experiencing hypoxia. You don't have problems with the enzyme unless there are issues with the bodies oxygen supply to cells. When you do the enzyme triggers angiogenesis and, potentially, cancer so destroying the enzyme is a good thing.

PL-7 autoimmune antibodies are targeted against TARS1, which is in the cytoplasm. This is happening because you have high ATP in your cytoplasm which is well known in ME//CFS and magnesium deficiency.

ATP + L-threonine + tRNA(Thr) = AMP + diphosphate + H+ + L-threonyl-tRNA(Thr)

You body is trying to slow down your TARS1 enzyme because of the high levels of ATP in you cytoplasm.

Not all autoimmune conditions are a good thing though, as some factors can simply cause a dysregulation of immune function. But I agree with you about the majority of cases.

I disagree with this. All autoimmune diseases are the body protecting itself in a last ditch effort to fix a metabolic problem.

I have been taking a bunch of supplements for my condition, including magnesium, and my condition has mildly improved. Since learning that a lot of genetic variations, and most diseases, are related to imbalances in the microbiome I have been gradually transitioning to a diet high in prebiotics for healthy bacteria as well as anti-microbial and anti-biofilm substances to help kill off pathogenic bacteria. Since no one has a definitive answer for repairing dysregulated GABA receptors, as occurs in benzodiazepine withdrawal, I am just hoping that rebuilding the microbiome will gradually normalise GABA function.

This is the hard part. Because if you are still drinking coffee or doing anything else that stimulates GABA release it will take longer and this is even true with pre and probiotics since they will increases GABA in the colon. As I have spoken with people in recovery I see them engaging in GABA seeking even though they do not know it (sugar, coffee, smoking) and all it is doing is delaying recovery.

Beneficial effects of GABA-producing potential probiotic Limosilactobacillus fermentum L18 of human origin on intestinal permeability and human gut microbiota

Gamma-aminobutyric acid (GABA) is a non-protein amino acid with neuroinhibitory, antidiabetic, and antihypertensive properties and is used as a drug for treating anxiety and depression. Some strains of lactobacilli are known to produce GABA and strengthen ...

www.ncbi.nlm.nih.gov

And I would also advise only taking magnesium since supplementing with things like B6 could increase GABA.

Unfortunately, I feel the only answer is though.

 

[Baz493]

Essentially you're correct. My impaired respiratory function and low provision of oxygen to cells means that ATP isn't being used as it normally would be in the krebs cycle. That's likely to leave me with elevated ATP levels. However it's a chicken or the egg question regarding whether the respiratory issues or the ATP issues came first. What I do know is that I experienced severe muscle damage when I collapsed at work from heat stroke and this appeared to reduce the uptake of oxygen from my blood, meaning that a loss of myoglobin occurred. Iron supplements haven't significantly improved this and my bloodstream has almost constant 100% oxygen levels despite the respiratory issues. I am considering taking baking soda once I'm sufficiently recovered to try to trigger normal respiratory function through elevating my carbon dioxide levels, hopefully triggering normal breathing responses.

The issue with benzodiazepine withdrawal isn't the levels of GABA but the sensing of it by the GABA-A receptors. I haven't been able to find any research exploring how to repair receptor function after benzodiazepines have caused overactivation of them. GABA reduces excitatory response so overactivation of the receptors leads to reduced muscle responsiveness, reduced cognitive function, and a wide variety of other issues. My condition has gradually improved over the last five years, since the worst of the withdrawal eased after five years, but I am still largely incapacitated.

Regarding the causes of autoimmune disease I used to believe that all such conditions were positive responses but, in researching my own condition, I have read about certain conditions where autonomic nervous system dysfunction triggers a dysregulated production of autoimmune antibodies. In such situations the dysregulated signaling seems to confuse the immune system, resulting in production of unnecessary antibodies. Either way, since there seems to be feedback between the autonomic system and the spleen I am hoping that the baking soda, once I am reasonably recovered, will help to reset my autoimmune disease as well. Before you warn me I know the risks of taking too much; with consequences as bad as not trying it at all.

 

[Lasse]

Many are talking about GABA and benzodiazepines so I hope that this article is of interest.

Investigation into mechanisms mediating the inhibitory effect of 1,4-benzodiazepines on mast cells by gene expression profiling

 

[Lasse]

Mast Cell Activation may cause all the symptoms of ME/CFS, but what is causing the Mast Cell Activation?

I believe it is high levels of ADP inside the cell and high levels of ATP outside the cell.

You see ADP triggers mast cell de-granulation, so the more ADP the more de-granulation you will have when your body senses an allergen.

P2Y13 receptor is responsible for ADP-mediated degranulation in RBL-2H3 rat mast cells

And high ATP outside the cell also primes MAST cells for de granulation.

Extracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors

But I think I would better say it is from a high ADP:ATP ratio inside the cell and a low ATP:ADP ratio outside the cell.

This might be a good read for everyone:

P2 receptor-mediated signaling in mast cell biology

And I can see this expressed in the opposite way for myself. I know I have a low of intercellular ATP and I have zero allergies.

Interesting I have to familiarize myself with the articles you have posted here about ATP.

Mast cell activation (MCA) is a common function of the immune system.
But several mutations in the mast cells can make them dysfunctional so that they can become overactive and hypersensitive.

Common triggers that can trigger illness are viruses, bacteria, parasites, mould, physical or mental stress, toxins/poison, heavy metals.

Several different mast cell diseases have been found that can look like ME/CFS and all are new with the exception of Systemic Mastocytosis. There is a possibility of new mast cell diseases in the future that we have not yet discovered.

Systemic Mastocytosis (SM) has been known since 1936. A rare immunological disorder that exists in many variants where the advanced variants are fatal. Around 90% have the D816V KIT mutation. Several mutations in KIT are common, but only D816V KIT can currently be tested in laboratories that are not research laboratories.
The KIT gene is on the tyrosine kinase receptors on the mast cell.

Monoclonal mast cell activation syndrome (MMAS) is a rare and little-known immunological disorder caused by mutations in the KIT gene, KIT D816V mutation is common. Patients with MMAS will not meet the full criteria for systemic mastocytosis.

Mast cell activation syndrome (MCAS) is thought to be very common and is caused by mutations in the KIT gene. More than 50 mutations found to date and those with MCAS often have several of these mutations.

Hereditary Alpha Tryptasemia Syndrome (HαTS) is a newly discovered common Mast Cell disease caused by an increased copy number α-tryptase-encoding regions on the TPSAB1 (TPSAB1) gene.

NIH: Genetic explanation uncovered with links to ME/CFS symptoms


Our unifying hypothesis of the pathophysiology of ME/CFS provides clues on possible mechanisms linking ME/CSF with MCA, dysmenorrhea, POTS, decreased cerebral blood flow and small fiber neuropathy. We are convinced that in all these syndromes, similar pathomechanisms are operative that not only explain the causes of each disease but also their frequent association.

Source National Institutes of Health (NIH):
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?

 

[Lasse]

Very interesting reading. I have all of the comorbitities listed except IC. And I believe that MCAS played a large part in all of my issues. But I still firmly believe that a viral infection started the whole cascade of symptoms. Very good info!

That is correct. Even if you are born with the gene mutations that can cause MCAS or other mast cell diseases, you need a trigger to activate the disease. The most common triggers for activating the disease are viruses, bacteria, parasites, mould, physical or mental stress, toxins/poison, heavy metals. Many people with mast cell diseases already have certain signs as children, long before they become ill. It may be that they easily get flu or other illnesses or often have a stomach ache, allergy, asthma or other mast cell-related illnesses.

From BBC:
'Long Covid triggered our MCAS, but doctors didn't believe us'
From LymeDisease.org
Mast Cell Activation Syndrome

 

[Lasse]

ME/CFS Muscle spasms and restless legs (RLS)
Muscle pain is sometimes accompanied by visible twitchings (= fasciculations), cramps and spasms. Some people with ME/CFS also have ‘restless legs syndrome’ – a fairly common complaint that may be associated with sleep disturbance, but can also be linked to iron deficiency anaemia.

Source: meassociation.org.uk

Mast Cell and restless legs (RLS)
This study shows that RLS appears to be associated with MCAS. Inflammation, immune mechanisms, autonomic dysfunction, and/or CNS hypoxia induced by MCAS may play pathophysiologic roles in this form of RLS. The circadian release of mediators from MCs in the evening may also have a direct relationship to RLS.

Source: Restless legs syndrome is associated with mast cell activation syndrome

Restless legs syndrome is associated with long-COVID in women

ME/CFS Psoriasis
Psoriasis significantly increases the risk of CFS, especially in men and the aging population. These increased risks can be attenuated in patients who receive phototherapy or immunomodulatory drugs.

Source:
Increased risk of chronic fatigue syndrome following psoriasis: a nationwide population-based cohort study

Mast Cell Psoriasis
The mast cell is a long-lived cell located at the upper dermal skin, which is activated and recruits other immune cells to induce an inflammatory response in psoriasis

Source:
Immune Cell Infiltration Analysis Demonstrates Excessive Mast Cell Activation in Psoriasis

ME/CFS and Autism Spectrum Disorder (ASD)
Many specialists who work with autism as well as CFS and fibromyalgia — myself included — find that there is a major overlap between the three conditions. I suspect all three have related underlying processes and, given a specific genetic makeup, the very same processes that trigger CFS and fibromyalgia in adults can trigger autism in children.

Source: Is Autism Related to CFS and Fibromyalgia?

Mast Cell and Autism Spectrum Disorder (ASD)
Many children with ASD have a history of “allergic symptoms”, often in the absence of mast cell (MC)-positive tests. Activation of MCs by various stimuli may release molecules related to inflammation and neurotoxicity, contributing to the development of ASD.

(mast cell (MC)-positive tests = IgE antibody test)

Source: Mast Cells in Autism Spectrum Disorder—The Enigma to Be Solved?

Mast Cells, Stress, Fear and Autism Spectrum Disorder
The mast cells - Cytokines axis in Autism Spectrum Disorder
Autism Spectrum Disorders and Mastocytosis

ME/CFS and neurologic and psychiatric symptoms (NPS)
However, ME/CFS is not a psychiatric disorder. It is officially classified by the World Health Organization (WHO) as a neuro-immunological disease. The condition involves a multitude of somatic dysfunctions and impairments that affect various systems simultaneously.

Source:
Identifying the mental health burden in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients in Switzerland: A pilot study

Mast Cell and and neurologic and psychiatric symptoms (NPS)
In studies over the last decade, at least 40–60% of MCAD patients exhibited NPS (Table 2) (Hermine et al., 2008, Smith et al., 2011, e30, e31, e32, e33, e34, e35), whereas the prevalence of NPS in the general population is below 10% (e30). The exact mechanisms that underlie NPS in MCAD are not yet understood in detail, but causal involvement of acute or chronic excessive MC activation seems certain.

Source:
Mast cell activation disease: An underappreciated cause of neurologic and psychiatric symptoms and diseases

Mast Cell Activation Syndrome: An Alert to Psychiatrists

 

[csinclair02]

I don't have any allergies as far as I know. I don't have any of the symptoms of MCAS. I doubt ME/CFS is caused by MCAS.

 

[Lasse]

I don't have any allergies as far as I know. I don't have any of the symptoms of MCAS. I doubt ME/CFS is caused by MCAS.

Same here, I don't have any allergies either.
I think many people misunderstand the symptoms of MCAS to be allergic symptoms.
Many people with MCAS have no hint of allergy (Click here for Video).

MCAS can have exactly the same symptoms as ME/CFS. If you search MCAS and your symptoms I am sure you will also find your symptoms with MCAS. See list of common symptoms of MCAS below.

Mast cell can not give you common allergy, they can only give you the symptoms of allergies.

Mast cell can give you Non-IgE-mediated allergy that does not show up on allergy tests.
These can be intolerances to things you eat such as food, medicines and chemicals as in Multiple Chemical Sensitivity.

Common allergy that can be tested for (IgE-mediated allergy) occurs when a protein from, for example, pollen attaches to a unique IgE receptor on a B cell. The B cell will then merge with a T cell and form a plasma cell that becomes a factory that mass produces and releases IgE receptors that are identical to the IgE receptor the pollen protein attached to. These IgE receptors will attach to the surface of mast cells and when such a protein comes into contact with a corresponding IgE receptor on mast cells, it will cause the mast cells to degranulate and release inflammatory mediators, mainly Histamine H1, which causes an allergic reaction.

As with ME/CFS, MCAS is an individual disease and the symptoms can vary from person to person. Some have some of the symptoms below, others have many of the symptoms below and some will also have symptoms that are not named below.

MCAS Systems by Organ System:

• Eyes: Red eyes, irritated eyes, dry eyes, burning eyes, difficulty focusing vision, and conjunctivitis (pink eye).
• Nose: Nasal stuffiness, sinusitis, postnasal drip, hoarseness, laryngitis, nose bleeds (epistaxis), and intranasal sores.
• Ears: Ringing in ears (tinnitus) and Eustachian tube dysfunction (blocked, popping ears).
• Throat: Vocal cord dysfunction, throat swelling, sores on tongue/mouth, itchy throat, burning mouth, dry mouth, and difficulty swallowing.
• Skin: Hives, angioedema (swelling of the skin), skin flushing, itching, skin rashes, dermatographism (when scratched skin causes a red welt), chronic itching, urticarial pigmentosa (legion/hive-like spots on the skin), flushing, bruising easily, reddish or pale complexion, cherry angiomata (skin growths), patchy red rashes, red face in the morning, cuts that won’t heal, fungal skin infections, and lichen planus.
• Cardiovascular: Fainting, fainting upon standing, increased pulse rate (tachycardia), palpitations, spikes and drops in blood pressure, high pulse or temperature, high triglycerides, lightheadedness, dizzy, hot flashes, and postural orthostatic hypotension syndrome (POTS).
• Respiratory: Wheezing, asthma, shortness of breath, difficulty breathing deeply, air hunger, dry cough, chronic obstructive pulmonary disease (COPD), and chronic interstitial fibrosis.
• GI Tract: Left upper abdominal pain, splenomegaly (enlarged spleen), epigastric tenderness, nausea, vomiting, diarrhea and/or constipation, abdominal cramping, bloating, non-cardiac chest pain, malabsorption, GERD/acid reflux, cyclic vomiting syndrome, colonic polyps, and gastric polyps.
• Liver: High bilirubin, elevated liver enzymes, and high cholesterol.
• Neurological: Numbness and tingling (especially in the hands and feet), headaches, migraines, tics, tremors, pseudo-seizures, true seizures, waxing and waning brain fog, memory loss, poor concentration, difficulty finding words, and spells of cataplexy (suddenly becoming disconnected from and unresponsive or unreactive to the world around).
• Musculoskeletal: Muscle pain, fibromyalgia, increased osteopenia, osteoporosis, weakness, and migratory arthritis (joint pain).
• Coagulation: History of clots, deep vein thrombosis, increased bruising, heavy menstrual bleeding, bleeding nose, and cuts that won’t stop bleeding.
• Blood disorders: Anemia, increased white blood cell count, platelets, decreased white blood cell counts, decreased neutrophils, decreased lymphocytes, decreased platelets, reductions in CD4 helper lymphocytes, reductions in CD8 positive suppressor lymphocytes, reductions or excesses of IgA, IgG, IgM, IgE, a known condition called MGUS, myelodysplastic syndrome (reduced red cells, white cells, platelets), and increased MCV (mean corpuscular volume).
• Psychiatry: Anxiety, panic, depression, obsessive compulsive disorder (OCD), decreased attention span, attention deficit/hyperactivity disorder (ADHD), forgetfulness, and insomnia.
• Genitourinary: Interstitial cystitis, recurrent bladder infections, sterile bladder infections, and frequent urination.
• Hormones: Decreased libido, painful periods, heavy periods, infertility, and decreased sperm counts.
• Dental : Deteriorating teeth.‍
• Anaphylaxis: Difficulty breathing, itchy hives, flushing or pale skin, feeling warm after exposure, weak and rapid pulse, nausea, vomiting, diarrhea, dizziness and fainting.

Some MCAS Triggers:

• Environmental Factors
  • Temperature shifts, including extreme heat or cold
  • Skin friction (such as that caused by massage)
  • Vibrational forces
  • Electromagnetic frequencies
  • Presence of mold
  • Insect sting venom, particularly from hymenoptera like wasps, bees, hornets, and ants
  • Exposure to heavy metals
  • Sunlight exposure / Ultraviolet (UV) light
  • Light / Flickering lights
  • Sounds / Noise
  • Potent scents or fragrances / Smoke
• Dietary Influences
  • Any food or beverage
  • Histamine-rich foods such as aged cheeses, fermented products, and certain fish
  • Foods containing salicylates
  • Alcoholic beverages
  • Artificial additives, colors, and preservatives
  • It's crucial to identify specific dietary triggers through detailed food trials under medical supervision, as even foods with low histamine levels may cause reactions.
• Medications
  • Antibiotics, with Vancomycin highlighted as a significant trigger, should be used with caution
  • Opioids, NSAIDs, neuromuscular junction blocking agents, and local anesthetics
  • Aspirin may be beneficial or harmful, necessitating strict medical supervision during trials
• Pathogens
  • Infections from bacteria, viruses, parasites, and mycotoxins from mold
• Stress
  • Emotional, physical, and social stressors: Stress, whether emotional, physical, or even due to sleep disturbances, can significantly impact mast cell activity. Learning stress management techniques can be a crucial part of managing MCAS.
• Hormone fluctuations
  • Women with MCAS may notice a pattern in symptom fluctuation correlating with menstrual cycles, pregnancy, or menopause, suggesting that hormonal changes can influence mast cell behavior. Sometimes this is diagnosed as PMDD, but more often these symptoms are incorrectly dismissed by doctors as normal symptoms of PMS.