Mast Cell Activation Syndrome (MCAS) and Mastocytosis

Mast cell activation syndrome (MCAS), is an immunological condition in which mast cells mistakenly release too many chemical mediators, resulting in several chronic symptoms involving the skin, gastrointestinal tract, heart, respiratory, and neurologic systems. Mast cells are present throughout most of our bodies and secrete different chemicals during allergic reactions. Symptoms include episodes of abdominal pain, cramping, diarrhea, flushing, itching, wheezing, coughing, lightheadedness and potential problems with "brain fog" or other difficulties with memory.

Mastocytosis occurs when too many mast cells accumulate in the skin and/or internal organs such as the liver, spleen, bone marrow, and small intestines. Mast cells are a type of white blood cell in the immune system.

People affected by mastocytosis are susceptible to a variety of symptoms, including itching, hives, and anaphylactic shock, caused by the release of histamine and other pro-inflammatory substances from mast cells.

Because mast cells play a role in allergic reactions, the symptoms of mastocytosis often are similar to the symptoms of an allergic reaction. They may include, but are not limited to:

  • Fatigue
  • Skin lesions (urticaria pigmentosa), itching, and dermatographic urticaria (skin writing)
  • Abdominal discomfort
  • Nausea and vomiting
  • Diarrhea
  • Olfactive intolerance
  • Ear/nose/throat inflammation
  • Anaphylaxis (shock from allergic or immune causes)
  • Episodes of very low blood pressure (including shock) and faintness
  • Bone or muscle pain
  • Decreased bone density or increased bone density (osteoporosis or osteosclerosis)
  • Headache
  • Depression
  • Ocular discomfort
  • Increased stomach acid production causing peptic ulcers (increased stimulation of enterochromaffin cell and direct histamine stimulation on parietal cell)
  • Malabsorption (due to inactivation of pancreatic enzymes by increased acid)[5]
  • Hepatosplenomegaly

 

https://media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnri2782/MediaObjects/41577_2010_Article_BFnri2782_Fig3_HTML.jpg

Everyone has mast cells in their body, and they play many complex roles in keeping us healthy. Mast cells are immune system cells that can be found in the bone marrow and body tissues, internal and external, such as the skin, gastrointestinal tract, the lining of the airway, and intestines. 

These cells help by playing a role in the immune defense against by helping our body protect us from infection and also playing an active role in the inflammatory process. Mast cells also involved in an allergic reaction. This can range from a tiny papule from a mosquito bite or a full-blown anaphylactic reaction.

By releasing chemical "alarms" such as histamine, mast cells attract other key players of the immune defense system to areas of the body where they are needed

In someone with mast cell disease, mast cells may activate inappropriately in response to triggers, or may also be proliferate and accumulate in organ tissues (Jennings & Slee 2020-2021).

Mast cells express a cell surface receptor, c-kit (CD117), which is the receptor for stem cell factor (scf).

https://www.researchgate.net/publication/321380644/figure/fig2/AS:566838121959425@1512156147638/Mast-cell-related-disorders-Diseases-associated-with-mast-cells-can-broadly-include.png

MCAS

An important gene associated with Mast Cell Activation Syndrome is CHIT1 (Chitinase 1).

https://callisto.ggsrv.com/imgsrv/FastFetch/UBER1/ZI-3155-2016-ANN00-IDSI-19-1

This enzyme may play a role in the degradation of chitin-containing pathogens and participates in the defense against nematodes and other pathogens including viruses, bacteria, and fungi.-

In plants, chitinases this may be related to pathogen resistance. Chitinases occur naturally in many common foods. Bananas, chestnuts, kiwis, avocados, papaya, and tomatoes, for example, all contain significant levels of chitinase, as defense against fungal and invertebrate attack.

Human chitinases may explain the link between some of the most common allergies (dust mites, mold spores—both of which contain chitin) and worm (helminth) infections (worms have chitinous mouthparts to hold the intestinal wall).

Chitinases have a wealth of applications, some of which have already been realized by industry. This includes bio-conversion of chitin to useful products such as fertilizer, the production of non-allergenic, non-toxic, biocompatible, and biodegradable materials (contact lenses, artificial skin and sutures with these qualities are already being produced) and enhancement of insecticides and fungicides.

Possible future applications of chitinases are as food additives to increase shelf life, therapeutic agent for asthma and chronic rhinosinusitis, as an anti-fungal remedy, an anti-tumor drug and as a general ingredient to be used in protein engineering.

N-acetylglucosamine (GlcNAc) is the monomer of the polysaccharide chitin.-

Chitin, or N-acetyl glucosamine (CCG), inhibited induced systemic anaphylactic shock and ear swelling responses. IgE-mediated PCA was also inhibited by the oral administration or topical application of CCG. Histamine and β-hexosaminidase release from mast cells was decreased with the treatment of CCG. CCG also inhibited phorbol 12-myristate 13-acetate and calcium ionophore A23187-induced interleukin-1β production and mRNA expression by suppressing NF-κB activation and IκBα phosphorylation. Furthermore, CCG suppressed the activation of caspase-1. These results suggest that CCG may have beneficial applicability as a candidate for an anti-allergic agent.

There is evidence that N-acetylglucosamine stimulates the human fungal pathogen Candida albicans.

However, this may be ‘counterbalanced’ by the addition of β-glucan.

Recognition of exposed β-glucan by Dectin-1 receptor appears to severely limit Candida GI fitness and hence represents a promising target to reduce fungal colonization in patients at risks of systemic candidiasis.

N-Acetyl Glucosamine has anti-inflammatory effects in vivo by suppressing the activation of mast cells.

N-Acetyl Glucosamine (Nag) is required for Chitinase 1 in relation to MCAS.

Chitinase 1, in part, is regulated by PGLYRP1.

Peptidoglycan recognition protein 1 (PGLYRP1) plays an important role in the innate immune response. It is bactericidal against gram-positive bacteria such as S. aureus, S. epidermidis, and L. monocytogenes and generally has proinflammatory effects, inducing TNF-a and IFN-g in many tissues. 

PGLYRP-1 is also known to form a cytotoxic complex with HSP-70, suggesting it may also have a role in anti-cancer defense. 

As a pathogen recognition protein with antimicrobial properties, PGLYRP-1 is suspected to play an important role in maintaining the gut microbial flora.

By regulating TNF-a and HSP-70 we can mitigate the proinflammatory effect of PGLYRP1 and reduce the prolonged secretion of inflammation.

TNF-alpha is crucial for the development of Mast Cell. 

The proinflammatory cytokine TNF-alpha is rapidly released by mast cells after degranulation. 

TNF-alpha inhibition reduces mast cell numbers, and mast cell activation.

Ginger extracts have been reported to have anti-inflammatory, anti-oxidant, and anti-cancer effects. [6]-shogaol was shown to suppress the release of pro-inflammatory cytokines and decreased the level of inducible nitric oxide syntheses (iNOS), cyclooxygenase-2 (COX-2), and phospho-NF-kB. In addition, [6]-shogaol treatment also increased the expression of heat-shock protein (HSP)70. The neuroprotective, neurotrphic, and anti-inflammatory properties of [6]-shogaol may be translated to improvements in neurological performance. [6]-Shogaol's ability to inhibit HDAC was comparable to that of commonly used HDAC inhibitors Trichostatin A and MS275. [6]-shogaol can significantly attenuate a variety of neuroinflammatory responses by inducing HSP70, which is associated with HDAC inhibition in cortical astrocytes. Ginger also inhibits the activation of tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and inducible nitric oxide synthase (iNOS).-

Compounds for TNF Gene - From: DrugBank, PharmGKB, ClinicalTrials, ApexBio, DGIdb, HMDB, Tocris, and Novoseek:

Glycyrrhizin

  • Vinpocetine
  • Zinc (found in Shilajit)
  • Folate (found in Sea buckthorn)
  • Tanshinone IIA (Dan shen)

In addition, Skullcap inhibits TNF-a.

Resveratrol also inhibits TNF-a.

Pomegranate inhibits TNF-α-induced NF-κB activation and COX-2 expression.

Bladderwrack downregulated the SREBP-1c, FAS, TNF-α and IL-6 genes expression and activates Nrf2-inducing Heme oxygenase-1 (HO-1). Bladerwrack also relieves inflammation by reducing the transcriptional activity of the NF-κB.

Propolis suppressed the TNF-α and IL-6.

Prunella Vulgaris inhibited TNF-α, IL-6prostaglandin E2 (PGE2), NO production, systemic anaphylaxis, release of histamine in human mast cells, and decreased IgE-mediated local allergic reactions.

Ashwagandha significantly inhibited mRNA expression of inflammatory cytokines, including interleukin (IL)‑8, IL‑6, tumor necrosis factor (TNF‑α), IL‑1β and IL‑12, and promoted the mRNA expression of the anti‑inflammatory cytokine transforming growth factor (TGF)‑β1.

Withania somnifera (Ashwagandha) also results in normalization of glial fibrillary acidic protein (GFAP) expression as well as heat shock protein (HSP70), mortalin, and neural cell adhesion molecule (NCAM) expression.

Kudzu suppresses the production of inducible Nitric Oxide Synthase, Cyclooxygenase-2, Tumor Necrosis Factor-Alpha, and Interleukin-6 via inhibition of JNK, TBK1 and STAT1 in inflammatory macrophages.

Beta-glucan decreases the production and expression of TNF-alpha. In addition, it blocked activation of nuclear factor kappa B (NF-kappaB).

Sea Buckthorn (Hippophae rhamnoides) reduced NF-κB, Interleukin-1ß and Interleukin-6, and Tumor necrosis factor-α. Thus, the present data suggest that Sea buckthorn oil can be used as an anti-inflammatory and anti-psoriatic nutraceutical.

Chondroitin Sulfate inhibits secretion of TNF and CXCL8 from human mast cells stimulated by IL-33.

Fibrinolytic agent Nattokinase effectively dispersed established S. aureus biofilms and effectively killed bacterial cells being released from the biofilm. It was not cytotoxic and did not affect the host immune response. Levels of IL-6, IL-1β, and TNF-α were significantly decreased with Nattokinase.

Phosphatidylcholine significantly inhibits TNF-alpha, MAPKs, ERK, p38, NF-kappaB, and the killing of Mycobacterium tuberculosis in macrophages.-

Mannose Binding Lectin, which requires D-Mannose, inhibits TNF-alpha and attenuates evasion of pathogens by Innate Immune Responses.

Peptidoglycan recognition protein 1 (PGLYRP1) is also known as TNF Superfamily, Member 3 (LTB)-Like (Peptidoglycan Recognition Protein).

PGLYRP1 binding activates a bacterial stress response that causes the bacterium to shut down transcription and translation, and induces oxidative stress.

In mice, the lack of PGLYRP1 is associated with increased susceptibility to infectious disease, but also decreased susceptibility to autoimmune disease. The lack of PGLYRP1 was found to have increased susceptibility to corneal infections, reduced corneal wound healing, and increased scarification of the cornea when infected by P. aeruginosa. But PGLYRP1-deficient mice also had decreased severity of atopic dermatitis and contact dermatitis, and may play a role in the development of asthma.-

Among PGLYRP1 related pathways are Innate Immune System and Defensins. It may kill Gram-positive bacteria by interfering with peptidoglycan biosynthesis. Molecular function for PGLYRP1 includes zinc ion binding, which is found in Shilajit.

Compounds for PGLYRP1 Gene - From: HMDB and Novoseek:

L-Alanine (Glycine receptor agonist)

  • Shilijit contains Amino Acids:

Alanine

Arginine

Aspartic Acid

  • Cysteine
  • Glutamic Acid
  • Glycine
  • Histidine
  • Leucine

Methionine

  • Lysine
  • Proline
  • Serine
  • Threonine
  • Tyrosine
  • Valine
  • Another factor that heavily influences the function of PGLYRP1 is Betaine--Homocysteine S-Methyltransferase 2 (BHMT2).

Mast cells have a protective role in homocysteine-induced cardiac remodeling.

Compounds for BHMT2 Gene - From: DrugBank and HMDB:

Methionine (found in Shilajit)

  • Spermidine (found in Soy/Nattokinase)
  • Mastocytosis

An important gene associated with Mastocytosis is KIT (KIT Proto-Oncogene, Receptor Tyrosine Kinase), and among its related pathways/superpathways are ERK Signaling and PEDF Induced Signaling.

Compounds for Mastocytosis (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

Tannic acid

  • Compounds containing tannic acid:

Prunella vulgaris

Propolis

Dan shen

  • Ginger

Pomegranate

  • Resveratrol 
  • Ashwagandha
  • Kudzu
  • Skullcap
  • Sea buckthorn
  • Vinpocetine
  • C-Kit, or KIT Proto-Oncogene, Receptor Tyrosine Kinase, acts as cell-surface receptor for the cytokine KITLG/SCF and plays an essential role in the regulation of cell survival and proliferation, hematopoiesis, stem cell maintenance, gametogenesis, mast cell development, migration and function, and in melanogenesis.

Cis-retinoic acid (Vitamin A) upregulates KIT. 

KIT interacts (via phosphorylated tyrosine residues) with the protein phosphatases PTPN6/SHP-1 (via SH2 domain), PTPN11/SHP-2 (via SH2 domain).

SHP2 protein-tyrosine phosphatase (encoded by Ptpn11) positively regulates KIT (CD117) signaling in mast cells and is required for mast cell survival and homeostasis in mice.

SHP2 interacts with CEACAM1, which is the primary gene involved with the Innate Immune system.

Thus, SHP2 inhibitors may be useful to limit SCF/KIT-induced mast cell recruitment to inflamed tissues.

Protein Tyrosine Phosphatase, Shp2, Positively Regulates Macrophage Oxidative Burst.

PTPN11/SHP2 Modulators:

Resveratrol

Cryptotanshinone (Dan shen)

Ashwagandha

  • Licorice
  • Beta glucan
  • Shp2 functions downstream of Syk in Dectin-1 signaling. Upon treatment with the Syk inhibitor ROS production was strongly suppressed, which correlated kinetically with reduced Syk, Shp2, Erk, and Akt activation.

https://www.researchgate.net/profile/Yukihiro_Kimura3/publication/266026844/figure/fig7/AS:634147311734792@1528203909597/Dectin-1-mediated-signaling-in-mast-cells-may-directly-and-indirectly-contribute-to.png

 

Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses.

Fungal infection stimulates the canonical C-type lectin receptor (CLR) signaling pathway via activation of the tyrosine kinase Syk. Here we identify a crucial role for the tyrosine phosphatase SHP-2 in mediating CLR-induced activation of Syk. Ablation of the gene encoding SHP-2 (Ptpn11; called 'Shp-2' here) in dendritic cells (DCs) and macrophages impaired Syk-mediated signaling and abrogated the expression of genes encoding pro-inflammatory molecules following fungal stimulation. Mechanistically, SHP-2 operated as a scaffold, facilitating the recruitment of Syk to the CLR dectin-1 or the adaptor FcRγ, through its N-SH2 domain and a previously unrecognized carboxy-terminal immunoreceptor tyrosine-based activation motif (ITAM). We found that DC-derived SHP-2 was crucial for the induction of interleukin 1β (IL-1β), IL-6 and IL-23 and anti-fungal responses of the TH17 subset of helper T cells in controlling infection with Candida albicans. Together our data reveal a mechanism by which SHP-2 mediates the activation of Syk in response to fungal infection.

C-type lectin receptors (CLRs) are a large superfamily of proteins characterized by the presence of one or more C-type lectin-like domains (CTLDs). CLRs function as pattern-recognition receptors (PRRs) for pathogen-derived ligands in dendric cells, macrophages, neutrophils, etc., such as Dectin-1 and Dectin-2 for recognition of fungi-derived B-glucan and high mannose-type carbohydrates. Upon ligand binding, CLRs stimulate intracellular signaling cascades that induce the production of inflammatory cytokines and chemokines, consequently triggering innate and adaptive immunity to pathogens.

C-type lectin receptor signaling pathway - Homo sapiens (human)

Syk plays a critical role in FcεRI signaling in mast cells. High-affinity receptor for IgE (FcεRI) initiates a series of biochemical events in mast cells.

Syk activity might be effective to modulate NLRP3 inflammasome activation and treat NLRP3-related immune diseases.

Flexible Syk: turning on and off the inflammasome as needed.

Discovery of a Natural Syk Inhibitor from Chinese Medicine through a Docking-Based Virtual Screening and Biological Assay Study.

Natural SKY Inhibitors:

Piceatannol, a natural stilbene

tanshinone I (Dan Shen)

Ginger

  • Liquorice

Chinese skullcap

  • Resveratrol inhibited mast cell-derived, immediate-type allergic reactions, and these responses of resveratrol suggest possible therapeutic strategies in preventing allergic inflammatory diseases.

Danshen had anti-allergic activities; these components were able to directly inhibit mast cell degranulation and interfere with FcεRI-mediated tyrosine phosphorylation of PLCγ2 and MAPK. Danshen directly affects FcεRI expressing cells, such as mast cells, with activation of the CD23-induced negative signaling pathway for inhibition of IgE synthesis.

6-gingerol suppresses cytokine production for T cell activation and proliferation, thereby not causing B cell and mast cell activation and resulting in prevention or alleviation of allergic rhinitis symptoms. Ginger inhibits histamine release.

Chrysin, found in propolis, suppresses mast cell-mediated allergic inflammation and reduced histamine release from mast cells.

Licorice acts as a “mast cell stabilizer”, as it inhibited mast cell degranulation and decreased vascular permeability by inhibiting the expression of Orai1, STIM1 and TRPC1, which blocked extracellular Ca2+ influxes. It may serve as an effective anti-allergic agent derived from food for the prevention and treatment of IgE-mediated allergic reaction.

Skullcap alleviates allergic inflammation and mast cell-mediated anaphylactic shock by regulation of Th1/Th2 imbalance and histamine release. Wogonin as an active component of skullcap may be applied as a therapeutic agent for IgE- and IL-5-mediated allergic disorders.-

KITLG - Stem Cell Factor

KITLG is activated by HMGA1.

High mobility group box 1 protein (HMGB1) is secreted by immune cells (like macrophages, monocytes and dendritic cells) through leaderless secretory pathway, which depends on HSP70/DNAJ14.-

Activated macrophages and monocytes secrete HMGB1 as a cytokine mediator of Inflammation. Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritis, colitis, ischemia, sepsis, endotoxemia, and systemic lupus erythematosus.

The mechanism of inflammation and damage consists of binding to TLR2 and TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release. This positions HMGB1 at the intersection of sterile and infectious inflammatory responses.

HMGB1 is involved in the NLRP3 Inflammasome.

Inflammation is an important host response triggered by invading pathogens or damaged tissues, a response that is aimed at diluting or destroying the pathogens or isolating the involved site. Moderate inflammatory response contributes to the host defense by removing pathogens or aiding in the repair of damaged tissue. However, uncontrolled or prolonged inflammation may promote further tissue damage and could lead to serious disorders due to the overproduction of inflammatory cytokines.

NLRP3 inflammasome can be activated by a broad range of stimuli that belong either to pathogen-associated molecular patterns (PAMPs) released during viral, bacterial, fungal, or protozoa infection.

Propolis, Quercetin, Emodin, and Resveratrol, are natural compounds that regulate NLRP3 Inflammasome-Mediated IL-1β production.

Important genes associated with the HMGB1 network are-:

  • SLC2A3 - Mediates the uptake Mannose, and fucose (Bladderwrack), and probably also dehydroascorbate (Vitamin C).

CDKN2A - keep cells from growing and dividing too rapidly or in an uncontrolled way.

  • CDK inhibitors - Resveratrol, Genistein (Nattokinase/Kudzu), Licorice, Luteolin (Prunella vulgaris), Kaempferol, Quercetin, Chrysin (Propolis).
  • NFKB1 - a transcription regulator that is activated by various intra- and extra-cellular stimuli such as cytokines, oxidant-free radicals, ultraviolet irradiation, and bacterial or viral products. Activated NFKB translocates into the nucleus and stimulates the expression of genes involved in a wide variety of biological functions. Inappropriate activation of NFKB has been associated with a number of inflammatory diseases while persistent inhibition of NFKB leads to inappropriate immune cell development or delayed cell growth.
    • Compounds for NFKB1 Gene - From: DrugBank, ApexBio, DGIdb, HMDB, Tocris, and Novoseek: glycyrrhizin (Licorice), Kaempferol (Nattokinase/Glycine max, Rosmarinic acid/Prunella vulgaris, Ginger, ), Luteolin (Prunella vulgaris) , Emodin (Sea buckthorn), Tanshinone IIA (Dan shen), Caffeic acid phenethyl ester (Propolis), Withaferin A (Ashwagandha). 

TP53 (guardian of the genome)

  • Compounds for TP53 Gene - From: DrugBank, PharmGKB, ClinicalTrials, ApexBio, DGIdb, Tocris, and Novoseek: Vinpocetine, Zinc (Shilajit), Betulinic acid (Prunella vulgaris).
  • PPARG - Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels. PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis and cancer.
    • Compounds for PPARG Gene - From: DrugBank, PharmGKB, ApexBio, DGIdb, IUPHAR, HMDB, Tocris, and Novoseek: linoleic acid (Sea buckthorn), Resveratrol, oleic acid (Sea buckthorn), alpha-linolenic acid (Sea buckthorn), Palmitic Acid (Sea buckthorn/Coconut MTC), Capric acid (Coconut/MTC), Isoflavone (Nattokinase/Kudzu), Myristic acid (Sea buckthorn/Coconut). 

Johnny on the Spot-Chronic Inflammation Is Driven by HMGB1. 

HMGB1 released into the extracellular milieu and its persistence in the microenvironment can contribute to the pathogenesis of many if not all autoimmune disorders and is a key factor that drives inflammation further and worsens symptoms. HMGB1 is also pivotal in the maintenance of chronic inflammation and a “wound healing”. HMGB1 can activate and recruit mast cells. 

ReverseFX is “Johnny on the Spot” when it comes to all things Mast Cell related!

All Rights Reserved. ©2020.

This is intended for education, research and data collection. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. The information provided on this site is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional or any information contained on or in any product label or packaging. You should not use the information on this site for diagnosis or treatment of any health problem or for prescription of any medication or other treatment. You should consult with a healthcare professional before starting any diet, exercise or supplementation program, before taking any medication, or if you have or suspect you might have a health problem. You are solely responsible for doing your own research on any information provided. This should not substitute professional advice. Individual results may vary. Database references herein are not all inclusive. Getting well from reading or using the information contained herein is purely coincidental. Any and all products or services may be subject to change.

Shop now

RESTORE THE DIVINE TEMPLATE OF THE IMMUNE SYSTEM

REVERSEFX