Long Covid Theory - Mast Cell Progenitors
Mast Cell Progenitors
2020-11-15
Long Covid is not only about people getting out of the ICU and taking time to heal. Long Covid is about a persistent condition that waxes and wanes for months in and months out. Some of the so called "long haulers" had symptoms of a common cold in the acute phase, were totally recovered for weeks, and then got hit by a freight train of various symptoms like dizziness, brain fog, numb limbs, fatigue, heart palpitations, skin rashes, inflammation, and much more.
How is this possible? I will present a theory that might just explain this phenomenon.
The coronavirus family can induce proliferation of mast cells in the respiratory mucosa [1]. In Covid-19, a high density of mast cell progenitors has been seen in the alveolar septa of post-mortem lung biopsies [2]. There was a remarkable increase of both mast cells and particularly mast cell progenitors compared to healthy controls and H1N1 infected cases.
How is this relevant to long covid?
I propose a theory where mast cell progenitors are recruited to the infected sites of sars-cov-2 where they granulate, degranulate, granulate, degranulate for months, causing various symptoms.
Mast cell progenitors originate from the bone marrow and circulate in the blood. Before they can become mast cells they need to find their way into tissue and mature by granulating various mediators like serine proteases, histamine, and serotonin. This takes time, quite a lot of time actually, in mice this takes about 2 to 3 weeks. How long does it take for human mast cells?
Long haulers have been reporting a strange interval of symptom flare ups. For many, this happens every fourth week, and this is reported by all genders, so it is not a hormonal thing.
Furthermore, Multisystem Inflammatory Syndrome in Children (MIS-C) has been reported to occur approximately three to four weeks after an often asymptomatic infection [3]. Could this be a coincidence?
The granulation time of human mast cells is not known by science today, but could it be a too long stretch to assume that it might be 3 to 4 weeks?
Mast cells can degranulate before they are fully mature as well if activated.
Lyme disease is known to have very similar symptoms as Long Covid, and it is known to wax and wane with an interval of 2 to 4 weeks. Could this be the same mechanism? In this case the toxins from bacteria could be the driver of mast cell activation.
After 3 to 4 weeks, long haulers are stuck with an overabundance of mature mast cells ready to degranulate. They can be triggered by various mechanisms, including IgE and IgG antibodies, toll-like receptors, stem cell factor receptors, complement receptors, cytokine receptors, neuropeptides, and opioids [4].
There are numerous reports about Interleukin-6 (IL-6) being high in covid patients. What happens to mast cells when IL-6 is high? Well, it promotes an increase in human mast cell number and reactivity [5].
To understand what symptoms mast cell activation could cause, let’s look at the unfortunate people that suffer from Mast Cell Activation Syndrome (MCAS), they have long been reporting these symptoms from mast cell activation [6]:
flushing
allergic-type issues
fatigue
dermatographism
cognitive dysfunction
irritated eyes/nose/mouth/throat
adenitis
dyspnea
palpitations
nausea
reflux
abdominal pain
diarrhea (often alternating with constipation)
interstitial cystitis
vulvovaginitis
menorrhagia
dysmenorrhea
fibromyalgia-type pain
joint hypermobility
benign growth anomalies (e.g. cysts, fibrosis, vascular anomalies, poor healing)
headache
sensory neuropathy
dysautonomias (e.g. orthostatic hypotension, blood pressure and heart rate lability, thermal dysregulation)
anxiety and mood disorders
assortment of metabolic/endocrinologic (e.g. thyroid)
I have personally read posts from long haulers about almost all of the symptoms above, and I have not read about many symptoms that are not in this list. Could this be a coincidence?
Many long haulers develop new food sensitivities or existing sensitivities are enhanced. This could be explained by new or old antibodies (IgG or IgE) attaching to the new mast cells.
Histamine intolerance is often reported by long haulers. Histamine is mediated by mast cells and exaggerates activation of other mast cells.
During my own long haul journey I had a lot of inflammation in my throat. This started a couple of weeks after my first symptoms. The inflammation was persistent and didn’t let up until after about 8 to 12 weeks. If the inflammation stemmed from the new mast cells, how long would you guess the half life of mast cells in mucosa would be? How about 40 days? This is the half life of mast cells in rat mucosa [7].
I see two possible explanations for this, first, not everybody’s immune system recruits mast cell progenitors to the infected sites, second, long haulers have more sensitive mast cells, i.e. are predisposed to MCAS, and are having problems with down-regulating mast cells in general.
This could be a mutation in the c-KIT gene, which is involved in controlling the lifecycle of mast cells.
It could also be a type I interferon dysfunction. A rare type I interferon impairment was found in about 10% of severely ill covid-19 patients [8]. Type I interferons are known to down-regulate mast cells [9].
Biopsies of covid toes have revealed an interferon alpha response in the tissue [10]. Could this be to down-regulate mast cells?
Mast cells are not easily measured. They are not circulating in the blood, and biopsies need to be done in order to analyse them. Not only that, the researchers need to know what they are looking for and use the correct staining for mast cells to reveal themself.
So what are the possible therapies for us long haulers? First of all we need to calm down our active mast cells. This is done with the same medications as for people that suffer with MCAS [11].
In the long run I believe that to cure our condition we need to down-regulate the number of mast cells we accumulated from the acute infection. Possible therapies could come from the various treatments of mastocytosis, a rare disease where mast cells are produced out of control by the body. Unfortunately there are no easy treatments that cure this condition. In our case time will surely regulate our bodies back to a more normal state.
The medication Interferon alpha-2b has been reported to successfully down-regulate mast cells in patients with aggressive systemic mastocytosis [12].
The chemically modified tetracyclines (CMT) could be a potential medication as well. Specifically the CMT-3 variant seems like a potent molecule for future studies [13].
Yours Sincerely
Christian T
longcovidtheory@gmail.com
[1] Mast cells contribute to coronavirus-induced inflammation: new anti-inflammatory strategy
[2] Mast Cells in Alveolar Septa of COVID-19 Patients: A Pathogenic Pathway That May Link Interstitial Edema to Immunothrombosis
[3] Coronavirus disease 2019 (COVID-19): Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis
[4] Mast cells: Surface receptors and signal transduction
[5] IL-6 promotes an increase in human mast cell number and reactivity through suppression of SOCS3
[6] Diagnosis of mast cell activation syndrome: a global “consensus-2”
[7] Long term increase of mucosal mast cells in the rat induced by administration of Compound 48/80
[8] Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients
[9] Type I interferon limits mast cell–mediated anaphylaxis by controlling secretory granule homeostasis
[10] Clinical, Laboratory, and Interferon-Alpha Response Characteristics of Patients With Chilblain-like Lesions During the COVID-19 Pandemic
[11] MAST CELL ACTIVATION SYNDROME (MCAS)
[12] Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature
[13] Chemically modified tetracyclines induce apoptosis in cultured mast cells