The Provider Primers Series: Introduction to Mast Cells

Mast cells : Introduction

  • Mast cells are bone marrow derived. They migrate to tissues before maturity and remain tissue bound.[i]
  • Mast cell development in tissues is regulated by a number of molecules, most significantly stem cell factor (SCF) which binds at the CKIT (CD117) receptor. A number of other molecules, including IL-3, IL-4 and IL-10, also participate in this process.[ii]
  • Mast cells are long lived, with some living for years in tissue.[ii]
  • Mast cells are versatile actors. Their functions and granule contents are tailored to the needs of the local microenvironment.[iii]
  • Mast cells perform a number of critical roles, including immune defense against microbes and larger parasites; clotting; wound repair; tissue remodeling; angiogenesis; regulation of reproductive cycle; digestion and GI motility; pain response; participation in stress response via interaction with HPA axis; inflammatory response; and regulation of sleep and some aspects of cognition.[iv]
  • Mast cells produce a multitude of mediators which are stored in granules or produced de novo. Stored mediators of consequence include histamine; tryptase; heparin; bradykinin; serotonin; and substance P. De novo mediators include prostaglandin D2; leukotrienes C4, D4, and E4; platelet activating factor; tumor necrosis factor; interferons; and a number of interleukins, including IL-1a, IL-1b and IL-6, among many others. [iii]

Mast cell involvement in disease

  • Mast cells are involved in the pathology of many conditions, including asthma[iv]; autoimmune diseases[iv]; GI dysmotility, including post-operative ileus[v]; cardiovascular events[iv], such as myocardial infarction, rupture of atherosclerotic plaques or aneurysms, and coronary syndromes, including Kounis syndrome[vi]; cardiovascular disease; malignant and neoplastic [iv]; chronic kidney disease[iv]; cutaneous conditions[iv], including many forms of urticaria; depression and anxiety; and chronic pain[vii].
  • Mast cells are effectors in all mast cell diseases.
  • Most famously, mast cells are involved in allergy and anaphylaxis.[viii]

Mechanisms of mast cell activation

  • Mast cells are primarily activated via IgE crosslinking at the FcεRI receptor. This is the mechanism for the classic allergy model in which specific IgE binds the target allergen and crosslinks at the FcεRI receptor on the surface of mast cells and basophils. In this traditional model, crosslinking causes immediate degranulation of stored mediators and late phase release of mediators produced de novo upon activation[viii].
  • There are several other mechanisms for direct mast cell activation that are independent of IgE.
  • A number of inflammatory molecules can directly activate mast cells by binding surface receptors including corticotropin releasing hormone; substance P; histamine; cysteinyl leukotrienes; adenosine; stem cell factor; IL-3; IL-4; IL-9; and IL-33, among others[ix].
  • Substances associated with immune defense and infection can directly activate mast cells. Products derived from pathogens can activate via toll like receptors (TLR2 and TLR4), Dectin-1 or CD48. Host production of β-defensins and complement C3a and C5a can also provoke mast cell activation[ix].
  • IgG can bind at FcγR receptors on mast cell surfaces. Immunoglobulin free light chains have triggered degranulation in murine models but this has not yet been demonstrated in humans[ix].

Definition of anaphylaxis

  • The definition of anaphylaxis continues to be disputed. The 2006 NIAID/FAAN criteria detailed below have been validated and are widely used.[x]
  • Anaphylaxis is likely when any one of the following three criteria is met:
  • Criterion 1: Acute onset of illness with skin and mucosal issue involvement (hives, itching, flushing, swelling of lips/tongue/uvula) with at least one of the following: compromised airway (difficulty breathing, wheezing, low blood oxygenation); or reduced blood pressure or symptoms thereof (fainting, incontinence.)
  • Criterion 2: Two or more of the following occurring after exposure to a likely allergen: skin or mucosal tissue involvement (hives, itching, flushing, swollen lips/tongue/uvula), compromised airway (difficulty breathing, wheezing, low blood oxygenation); reduced blood pressure or symptoms thereof (fainting, incontinence); or persistent GI symptoms (cramping, abdominal pain, vomiting).
  • Criterion 3: Reduced blood pressure after exposure to known allergen.  For adults, this is <90 mm Hg systolic, or at least 30% decrease from baseline.  For children under 1 year of age, this is <70 mm Hg systolic; ages 11-17, <90 mm Hg systolic.  For children 1-10 years of age, this is <(70 mm Hg + (2x age)).  So for a child who is 8 years old, this would be <(70 + (2 x 8)) = <86 mm Hg.

References:

[i] Dahlin JS, Hallgren J. (2015). Mast cell progenitors: origin, development and migration to tissues. Molecular Immunology 63, 9-17.

[ii] Amin K. (2012). The role of mast cells in allergic inflammation. Respiratory Medicine, 106, 9-14.

[iii] Theoharides TC, et al. (2012). Mast cells and inflammation. Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease, 1822(1), 21-33.

[iv] Rao KN, Brown MA. (2008). Mast cells: multifaceted immune cells with diverse roles in health and disease. Ann NY Acad Sci, 1143, 83-104.

[v] De Winter, BY. (2012). Intestinal mast cells in gut inflammation and motility disturbances. Biochimica et Biophysica Acta, 1822, 66-73.

[vi] Kounis NG. (2016). Kounis syndrome: an update on epidemiology, pathogenesis, diagnosis and therapeutic management. Clin Chem Lab Med, 54(10), 1545-1559.

[vii] Chatterjea D, Martinov T. (2015). Mast cells: versatile gatekeepers of pain. Mol Immunol, 63(1), 38-44.

[viii] Galli SJ, Tsai M. (2013). IgE and mast cells in allergic disease. Nat Med, 18(5), 693-704.

[ix] Yu Y, et al. (2016). Non-IgE mediated mast cell activation. European Journal of Pharmacology 778, 33-43.

[x] Sampson HA, et al. (2006). Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol, 117(2), 391-397.

Take home points: July 2015

Mast cell interactions with B and T cells
• Mast cells communicate with other cells by:
o Releasing chemicals to tell another cell to do something
o Other cells releasing chemicals to tell mast cells to do something
o Moving right up against other cells, which allows the cells to “talk”
• B cells are white blood cells that make antibodies and protect against infections.
o Mast cells can tell B cells to make IgE, an allergy antibody.
o When mast cells touch B cells, the mast cells can release IL-6 which tells B cells to live longer.
o Mast cells can tell B cells to make IgA, an antibody.
• T cells are white blood cells that have many functions.
o T cells and mast cells are found close together in many inflammatory conditions, like ulcerative colitis.
o Activated T cells can activate mast cells.
o Mast cells can tell T cells to proliferate and produce inflammatory molecules.
o A kind of T cell called Treg (T reg, like in regulatory) cells can make mast cells harder to activate and interfere with degranulation.

Mast cells in kidney disease
• Kidney disease is often not identified until 60-70% of functional kidney cells have been damaged beyond repair.
• Mast cells are rare in healthy kidneys.
o Damaged kidneys can have up to 60x the normal amount of mast cells.
o Mast cell count is not related to disease severity.
• Atopic disease, like atopic dermatitis and allergic asthma, is linked to idiopathic nephrotic disease, kidney disease of unknown origin.
o The nephrotic disease and atopic disease could be manifestations of the same overarching condition.
o In patients with both, IgE levels are high.
• Tryptase is elevated in some patients with kidney damage.
• Mast cells are responsible for bringing other inflammatory cells to the damaged kidney.
• Mast cells can cause fibrosis in kidneys.
• In some roles, mast cells can protect kidneys from damage.

Regulation of mast cells by IgE and stem cell factor (SCF)
• Mast cells are mostly regulated in two ways
• IgE binds to the IgE receptor (FceRI) on mast cells and activates them
o Activation by IgE results in degranulation and secretion of mediators
o IgE induces mediator release by affecting the amount of calcium inside mast cells
• Stem cell factor (SCF) binds to the CKIT receptor on mast cells and tells them to stay alive
o SCF also increases degranulation and production of cytokines
o SCF helps mast cells to adhere to other cells

Mast cells in vascular disease: Part 3
• Mast cells are involved in the formation and growth of aneurysms
• Activated mast cell populations are increased in vessels that rupture
• Chymase, a mast cell mediator, can degrade vessels and increase risk of rupture
• Leukotrienes contribute to aneurysm formation

Patient questions: Is mast cell disease autoimmune?

Autoimmune disease is when your body has an abnormal immune response to something that is a normal part of the body. There are more than eighty currently identified autoimmune diseases and they affect a significant population worldwide. At least 2% of women are estimated to have at least one autoimmune condition. Multiple sclerosis, rheumatoid arthritis and lupus are examples of autoimmune disease. Autoimmune diseases can affect small areas or multiple organs or targets throughout the body.

There are a number of possible causes of autoimmune disease. Some well supported theories include:
1. Molecular mimicry. This occurs when the body is exposed to an external danger and direct antibodies and immune defense against this danger. However, once the danger has been resolved, the antibodies and immune defense are directed toward damaging some normal part of the body that by happenstance looks like the dangerous thing. A classic example of this is development of rheumatic fever, PANDAS and other complications after a Streptococcus infection. The body makes antibodies to fight Strep, the Strep is killed and infection resolved, but the antibodies then attack things in the body that look like strep to the antibodies.
2. Genetic predisposition. Mutations and improper expression of genes that mediate tolerance, like HLA genes, can result in autoimmune disease. In these patients, these anomalies cause the body to fail to recognize itself as “safe”.
3. Cryptic determinants. This refers to the situation in which a hidden part of a normal structure in the body is not usually “seen” by the rest of the body. When that hidden part is exposed to the rest of the body, the immune system does not recognize it and attacks it, thinking it is dangerous. I imagine this as a waterway in a year of drought. A river has many small black rocks on the bottom. When the water is high, like most years, you cannot see these rocks. In a year of drought, the water level drops and you can the black rocks on the bottom. They were always a natural part of the riverbed, and they were always there, you just couldn’t see them. This can happen inside the body too. Sometimes your immune system sees things that were always there but not seen by it before.

The key feature unifying autoimmune diseases is that the immune system directly targets a part of the body that is normal and healthy. In lupus, the body makes antibodies that target the DNA inside our cells, which is not just normal but critically important to survival. It doesn’t target defective DNA, it targets regular old, keeps us alive, DNA.

Mast cell diseases are not autoimmune diseases. Mast cell diseases are not directly their attacks to a normal, healthy part of the body. In mast cell disease, mast cells are dysregulated and behave inappropriately. While this can damage parts of the body, this damage occurs due to the general inflammatory environment rather than because mast cells specifically targeted those parts of the body. Aberrant mast cells aren’t saying, “Quick, there’s an intruder in the liver! Let’s go get them!” when it’s just your regular liver hanging out. They are just so activated that mediator release could damage some cells in the liver, and in other places at the same time. The mast cell activation does not specifically target the liver in this scenario.

A confusing aspect of mast cell disease is that MCAS can occur secondary to autoimmune disease and many MCAS patients have autoimmune disease. In this patient population, the MCAS is probably induced by the inflammation caused by the autoimmune disease. Even still, while the primary autoimmune disease targets specific parts of the body, MCAS does not target specific parts of the body to attempt to destroy them.

The Sex Series – Part Six: Male pelvic dysfunction and mast cells

Chronic pelvic pain syndrome (CPPS) affects about 15% of male patients and 90% of patients with chronic prostatitis. Patients with these conditions experience pain in the pelvis, abdomen and genitalia, as well as urinary tract symptoms without evidence of infection. Pain can be intermittent or constant, and can interfere with daily activities including sitting, standing, urination and defecation.

CPPS also causes sexual symptoms. Painful ejaculation, erectile dysfunction, and other types of ejaculation dysfunction are all common in this patient group.  In one study, 40% of patients with CPPS were found to have erectile dysfunction.  In another, 72% of patients reported either erectile dysfunction or difficulty with ejaculation.

Pelvic floor dysfunction is a component of CPPS. Many of these patients have abnormally tense pelvic floor muscles, which can cause muscle spasm and obstruct bloodflow. CPPS patients are more likely than healthy controls to have vascular dysfunction associated with nitric oxide level. In a group of 146 patients with CPPS and verified pelvic floor spasm, 56% experienced painful ejaculation.  Visceral and myofascial pain and spasm of the muscles in the pelvic floor contribute to CPPS.  While pelvic floor dysfunction has been well researched for female patients, there are far fewer studies on pelvic floor dysfunction in men.  Biofeedback and pelvic floor physical therapy can resolve issues with erectile dysfunction and other sexual issues.

IL-17, expressed by special T cells called Th17 cells, is required to develop CPPS-like conditions in animal models. IL-17 triggers mast cell degranulation and secretion of many inflammatory molecules.  A number of mast cell mediators are elevated in patients with CPPS. IL-1b, TNF, IL-6 and IL-8 are higher in seminal fluid of these patients.  CCL2 and CCL3 expression is also increased. In the prostate of animals with a CPPS model, TNF, IL-17a, IFN-γ and IL-1b are all increased.

Tryptase has been found to induce pelvic pain. Levels of tryptase and carboxypeptidase A3 are higher in CPPS patients than in healthy controls.  Tryptase binds to a receptor called PAR2.  When tryptase binds to this PAR2 receptor, it is thought that it makes nerves oversensitive. If the PAR2 receptor is blocked, pelvic pain is mitigated.  In animal models where they cannot make tryptase-like products, pelvic pain does not develop in CPPS.

Nerve growth factor (NGF) is a mast cell mediator that has been implicated in CPPS. It is elevated in seminal plasma of CPPS patients and directly correlates with pain level. It is thought that NGF makes the peripheral nerves oversensitive and causes more nerve cells than usual to be present. NGF and tryptase were elevated in prostate secretions of most CPPS patients in a small patient group. Of note, NGF release occurs and increases weeks after initial symptoms.

In animal models, injecting cetirizine (H1 antihistamine) into the peritoneal cavity decreased pain by about 13.8%; ranitidine (H2 antihistamine), 6.1%; cromolyn, 31.4%. A combination of all three decreased pain by 69.3%. When cromolyn and cetirizine were used together, larger pain relief was achieved than when used individually, but this was not seen when using ranitidine and cromolyn together.  These data suggest that H2 signaling is not a major contributor in chronic pelvic pain in male patients.

Pelvic floor dysfunction is also common in heritable connective tissue diseases and is often present in hypermobile patients.

References:

Done JD, et al. Role of mast cells in male chronic pelvic pain. Journal of Urology 2012: 187, 1473-1482.

Roman K, et al. Tryptase-PAR2 axis in experimental autoimmune prostatitis, a model for chronic pelvic pain syndrome. Pain 2014: 155 (7), 1328-1338.

Cohen D, et al. The role of pelvic floor muscles in male sexual dysfunction and pelvic pain. Sex Med Rev 2016; 4, 53-62.

Murphy SF, et al. IL17 mediates pelvic pain in experimental autoimmune prostatitis (EAP). PLoS ONE 2015, 10(5) : e0125623.

 

Glossary of mast cell related terms: P-Z

Parasympathetic nervous system: Part of the autonomic nervous system.  Regulates digestion and other functions.

Prostaglandin D2 (PGD2): The dominant prostaglandin produced by mast cells.

9a,11b-PGF2: a breakdown product of prostaglandin D2; can be measured to assess level of mast cell activation

Platelet activating factor (PAF): a mast cell mediator that correlates with severity of anaphylaxis; induces degranulation and release of leukotrienes and prostaglandins

Postural orthostatic tachycardia (POTS): increase of 30 bpm or more when standing in the absence of orthostatic hypotension.

Premedication: taking medication in advance of an event in order to suppress an undesirable reaction during the event, such as premedicating before surgery

Pre-stored: as relates to mast cell biology, mediators that are made inside the cell and stored in granules to be released at a later time

Progenitor cell: a cell that develops into another type of cell

Proliferation: growth and expansion of a cell population

Prostaglandin: a type of eicosanoid with wide ranging biological effects; PGD2 is the prostaglandin most abundantly produced by mast cells

Protracted anaphylaxis: a long episode of anaphylaxis symptoms despite treatment

Rare disease: a disease that affects only a small amount of people in a population; in the US, defined as affecting 200,000 people or less in the US

Rebound: a resurgence of symptoms after quelling symptoms earlier

Receptor: a protein on the outside of cells that bind specific molecules, causing a specific action to occur

Secretion: the release of molecules from inside the cell to the outside environment without degranulation

Sensitization: production of IgE specific to an allergen without obvious allergic reaction to the allergen

Serotonin: a neurotransmitter released by a number of cell types, including mast cells

Smouldering systemic mastocytosis (SSM): a form of SM in which organ damage and failure could eventually occur; diagnosed when someone with SM has two or more B findings

Splenomegaly: swelling of the spleen

Stem cell factor (SCF): a mast cell growth factor; SCF binds to CKIT and tells mast cells to stay alive and make more mast cells

Sympathetic nervous system: Part of the autonomic nervous system.  Controls the fight or flight response

Systemic mastocytosis (SM): a proliferative mast cell disease in which too many mast cells are produced

Systemic mastocytosis with associated clonal hematologic non-mast cell lineage disease (SM-AHNMD): co-occurrence of SM with another proliferative blood cell disorder, such as essential thrombocythemia or chronic myelogenous leukemia

Tachycardia: rapid heartbeat

Third spacing: when fluid is forced out of a place the body can use it and becomes trapped, such as ascites or angioedema

TLR: toll like receptor; receptors on the outside of many cells (including mast cells) that activate immune response to infections

Telangiectasia macularis eruptive perstans (TMEP): a less common form of cutaneous mastocytosis.  Found almost exclusively in adults.

Tryptase: a mast cell mediator; when tested outside of a symptomatic episode, it is used to measure the baseline amount of mast cells present ; when tested during a symptomatic episode, it can be used to identify mast cell activation

Urticaria pigmentosa (UP): also called maculopapular cutaneous mastocytosis (MPCM).  The most common form of cutaneous mastocytosis.

Urticaria: hives

Wheal and flare response: a reaction marked by redness and raised, taut skin due to histamine release

Glossary of mast cell related terms: M-O

Mast cell: white blood cells with important roles in allergy, anaphylaxis and immune defense that live in tissues and only briefly circulate in the blood; also called mastocytes

Mast cell activation: a change in mast cell behavior that occurs following exposure to a trigger that may indicate allergy or infection; a state in which mast cells release mediators, both through degranulation and through secretion; in some instances, culminating in anaphylaxis

Mast cell disease: a disease that occurs due to fundamental error in mast cell proliferation or activation physiology

Mast cell disorder: used synonymously with mast cell disease

Mast cell leukemia: a very aggressive mast cell disease marked by massively excessive proliferation of mast cells, culminating in progressive organ failure

Mast cell sarcoma: a very aggressive mast cell disease that presents as a connective tissue tumor and progresses to mast cell leukemia

Mast cell stabilizer: a medication that decreases the likelihood of mast cell degranulation and mediator release

Mastocytic enterocolitis: the phenomenon of having too many mast cells in the GI tract; originally described as more than 20 mast cells/ high power field, but there is no consensus on how many mast cells in a field is too many

Mastocytoma: a benign mast cell tumor. Most frequently occurs on skin, but can occur elsewhere in the body.

Mast cell activation disease (MCAD): usually a catchall term for mast cell diseases, although some people exclude cutaneous mastocytosis from this category

Mast cell activation disorder (MCAD): an alternate term for mast cell activation syndrome (MCAS); a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators

Mast cell activation syndrome (MCAS): a non-proliferative mast cell disease that is usually diagnosed by detecting an elevation in mast cell mediators; occurs secondary to a known condition or idiopathically, in which no primary condition is identified; “primary” mast cell activation syndrome has its own name, MMAS

Mediator: a molecule released from a cell that has effects on the environment outside the cell; mast cells release dozens of mediators

Monoclonal mast cell activation syndrome (MMAS) : a mast cell disease diagnosed when a patient meets some criteria for SM but not enough for an SM diagnosed

Monophasic anaphylaxis: an anaphylactic event in which symptoms resolve following administration of medication and do not recur at a later time

Mutation: a change in the genetic sequence that can affect the way a gene is expressed, or in the way its gene product is made or functions

Myeloid: concerning cells that develop into granulocytes, monocytes, platelets or erythrocytes

Myeloproliferative neoplasm: a disorder caused by aberrant proliferation of a myeloid cell line, such as SM, myelofibrosis, essential thrombocythemia or polycythemia vera, among others

Neoplasm: an abnormal cell

N-methylhistamine: a breakdown product of histamine; can be tested for to assess mast cell activation

Oral allergy syndrome: An IgE reaction to raw fruits and vegetables that causes itching and swelling in the mouth and throat.

Orthostatic hypotension (OH): reduction of systolic blood pressure of more than 20 mm Hg or diastolic blood pressure of more than 10 mm Hg within three minutes of standing.

Orthostatic intolerance (OI): symptoms that occur when transitioning to a standing position

Naturally occurring mast cell stabilizers: Part 4

I mentioned resveratrol in the previous post under its broad classification as a phenol.  Looking more narrowly, resveratrol is a derivative of stilbene.  It is found in several foods, including grapes and berries like blueberries and raspberries.  Resveratrol can form oligomers, in which several of the same molecule are connected together.  One such oligomer is Gnetin H.  This product is isolated from Paeonia anomala and is used in Mongolian Chinese medicine.  It has been found to significantly impair mast cell degranulation and is effective at lower doses than resveratrol.  Gnetin H also decreased histamine secretion and production of TNF and IL-4, as well as COX-2 and PGE2 (not a typo, prostaglandin E2).

Polydatin is a precursor to resveratrol.  In a rat model, administration of polydatin was found to make the small intestine mucosa much less “leaky”.  It also inhibited hypersensitivity in the small intestine.  Importantly, it decreased degranulation by as much as 65% (determined by examining tissue with toluidine blue staining), and decreased histamine in both serum and intestinal mucosa.  Degranulation involves changes in calcium inside the mast cell and treatment with polydatin interfered with this process.  It also interrupted production of IgE by suppressing IL-4 secretion.  In another paper, polydatin was also found to suppress anaphylaxis in the mouse model of passive cutaneous anaphylaxis.

Hydroxytyrosol is a phenol derived from olive oil and olive leaves.  In nature, it occurs in the form of oleuropein, which can be broken down to hydroxytyrosol.  In a study that used β-hexosaminidase as a  marker for mast cell degranulation, both hydroxytyrosol and oleuropein inhibited activation in cells at high concentrations. This is promising but future research is needed.

In mouse and human mast cells, hypothemycin was found to interfere with activation of the CKIT receptor and the IgE receptor (FceRI).  This resulted in suppression of degranulation and production of cytokines, including IL-4.  This product was originally extracted from a mushroom of the Hypomyces genus.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Kim M, et al. Gnetin H isolated from Paeonia anomala inhibits FceRI-mediated mast cell signaling and degranulation. J Ethnopharmacol 2014 Jul 3; 154(3): 798-806.

Yang B, et al. Polydatin attenuated food allergy via store-operated calcium channels in mast cell. World J Gastroenterol 2013 Jul 7; 19(25): 3980-3989.

Yuan M, et al. Polydatin (PD) inhibits IgE-mediated passive cutaneous anaphylaxis in mice by stabilizing mast cells through modulating Ca2+ mobilization. Toxicol Appl Pharmacol 2012 Nov 1; 264(3): 462-469.

Persia FA, et al. Hydroxytyrosol and oleuropein of olive oil inhibit mast cell degranulation induced by immune and non-immune pathways.  Phytomedicine. 2014 Sept 25; 21(11): 1400-1405.

Naturally occurring mast cell stabilizers: Part 3

Coumarins are compounds that occur naturally in a number of plant species.  Several medications are derived from coumarins, including several anticoagulants, such as warfarin. They are notable for being fragrant.  Coumarin increases resorption of edema fluids.

Scopoletin is a coumarin present in the root structures of several species, including Urtica dioica (stinging nettle), Scopolia japonica (Japanese belladonna), chicory and passion flower.  In human mast cells, scopoletin interferes with production of TNF, IL-6 and IL-8.  It was found to inhibit NF-kB, which participates in the inflammatory response.

Artekeiskeanol A is a coumarin extracted from Artemisa keiskeana.  In traditional medicine systems, it is sometimes used to treat rheumatoid arthritis.  It suppressed degranulation, decreased production of TNF and IL-13.  Selinidin, a coumarin found in Angelica keiskei, suppresses IgE-initiated degranulation and decreases production of LTC4 and TNF. Rottlerin from the tree Mallotus philippensis attenuates IgE activation, degranulation of at least airway mast cells, and histamine release.

Cinnamic acid is a coumarin that decreased antigen stimulated degranulation in basophils, but similar action has not been recorded in mast cells.  It is most commonly extracted from cinnamon oil. A furanocoumarin found in Angelica dahurica inhibits action of COX-2 and 5-LO, decreasing production of PGD2 and LTC4, in addition to preventing degranulation.

Thunberginol A and B from Hydrangeae macrophylla inhibits histamine release from activated mast cells.  Thunberginol A prevents release of TNF and IL-4. In particular, thunberginol B is a potent mast cell stabilizer, suppressing degranulation from IgE or other causes.  It can also suppress production of IL-2, IL-3, IL-4, IL-13, TNF and GM-CSF when triggered by IgE.

Ellagic acid is found in nuts and fruit, such as strawberries, raspberries, pomegranate and walnuts. It interferes with IgE activation of mast cells and decreases release of histamine, TNF and IL-6.

Plant phenols have been reported to have medicinal effects for many years.  Magnolol and honokiol, two substance found in the bark of Magnolia obovata, can interfere with basophil degranulation as well as allergic response more generally.  Resveratrol is a phenol derivative present in berries, peanuts and grapes.  It is a potent supporessor of inflammatory mast cell products, including TNF, IL-6 and IL-8.  It also interferes with the structures required for degranulation and can also interfere with basophil degranulation.

Curcumin is another phenol derivative and is already quite popular in the mast cell community. (Disclaimer: I take turmeric, which contains curcumin.)  Curcumin has well described anti-inflammatory and anti-allergic benefits.  It inhibits mast cell and basophil degranulation and decreases release of IL-4 and TNF.  It also suppresses a popular lab model of allergy, passive cutaneous anaphylaxis.

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Moon PD, et al. Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkappaB/NF-kappaB signal cascade in the human mast cell line HMC-1. Eur J Pharmacol 2007 Jan 26; 555(2-3): 218-225.

Kishiro S, et al. Selinidin suppresses IgE-mediated mast cell activation by inhibiting multiple steps of Fc epsilonRI signaling. Biol Pharm Bull 2008 Mar; 31(3): 442-448.

Bheekha-Escura, Roy, et al. Pharmacologic regulation of histamine release by the human recombinant histamine-releasing factor. May 1999; 103(5): 937-943.

Hong J, et al. Suppression of the antigen-stimulated RBL-2H3 mast cell activation by Artekeiskeanol A. Planta Med 2009 Nov; 75(14): 1494-1498.

Naturally occurring mast cell stabilizers: Part 2

As discussed in the previous post, many flavonoids can modulate mast cell responses.  Luteolin, a flavone, has been studied for its powerful effects on inflammatory cells.  With prophylactic administration of this molecule, activation of mast cells and T cells can be prevented in a disease model for multiple sclerosis. Luteolin can also inhibit IgE-triggered degranulation as well as production of various mediators.  It is found in many foods, including celery, carrots, and chamomile tea.

Genistein, an isoflavone, prevents IgE-induced degranulation and histamine release.  It is a natural tyrosine kinase inhibitor, mostly activate against EGFR. It can be extracted from Genista tinctoria, also called dyer’s broom.  Several structurally related molecules also have mast cell modulating effects. Amentoflavone, from Ginkgo biloba and St. John’s Wort, decreases histamine release by mast cells. Ginkgetin, derived from Ginkgo biloba leaves, inhibits phospholipase A2, a mast cell mediator, and inhibits production of PGD2 by interfering with the COX-2 enzyme and of LTC4 by interfering with 5-lipoxygenase.

Emodin is an anthraquinone with a long history of use in herbal medicine traditions.  It boasts an array of anti-allergic activity and can inhibit the following IgE induced effects: mast cell degranulation; production of TNF, PGD2 and LTC4; and secretion of TNF and IL-6. It is under investigation for use in type II diabetes, where it can decrease the activity of glucocorticoids in obese animals and may treat insulin resistance.  Emodin can be found in rhubarb, frangula bark and other plants.

A number of other natural molecules also have mast cell stabilizing effects. Epigallocatechin gallate, found in higher quantities in white and green teas, as well as apples, onions and hazelnuts, can inhibit mast cell degranulation and LTC4 secretion.  Xanthones found in the juice and fruit of the purple mangosteen, Garcinia mangostana, decreased histamine release as well as PGD2, LTC4 and IL-6 from mast cells.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 2013 Oct-Dec; 27(4): 955-959.

Theoharides TC, Kempuraj D, Iliopoulou BP. Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Adv Exp Med Biol 2007; 601: 423-30.

Son JK, et al. Ginkgetin, a biflavone from Ginkgo biloba leaves, inhibits cyclooxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells. Biol Pharm Bull 2005 Dec; 28(12): 2181-4.

Lu Y, et al. Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochem Pharmacol 2011 Dec 1; 82(11): 1700-1708.

Kim DY, et al. Emodin attenuates A23187-induced mast cell degranulation and tumor necrosis factor-a secretion through protein kinase C and IkB kinase 2 signaling. Eur J Pharmacol 2014 Jan 15; 723: 501-506.

Naturally occurring mast cell stabilizers: Part 1

Warning: Naturally occurring molecules can interfere with medications or adversely affect disease state.  Please consult with your managing provider before adding supplements or drastically changing diet.

Flavonoid is a broad term used to describe certain plant derived metabolites. It can be used to refer to a variety of molecules, including isoflavonoids, neoflavonoids and anthoxanthins, which are categorized based on structure.  A number of flavonoids have been shown experimentally to modulate mast cell behavior and function as mast cell stabilizers.

Homoisoflavonone decreases production of PGD2 and leukotrienes B4 and C4 by downregulating COX-2 and 5-LO, the enzymes that make these molecules from arachidonic acid. It also interferes directly with the manufacture of IL-6 and TNF in mast cells stimulated by IgE (the traditional allergy pathway).  Homoisoflavonone can be isolated from bulbs of Cremastra appendiculata, which is commonly called Chinese tulip despite being an orchid.  Chinese tulip is commonly used in Chinese medicine.  Related homoisoflavonoids, extracted from the tuber of Ophiopogon japonicas, mondograss, are anti-inflammatories, possibly by interfering with COX-2 and 5-LO.

Flavonols have been noted for their anti-allergic activity for a number of years.  Morin is a flavonol found in natural sources like Maclura pomifera (Osage orange) and Psidium guajava (guava).  Morin prevents mast cell degranulation and manufacture of cytokines like TNF and IL-4, as well as suppressing IgE activation almost completely at higher doses (please note the study on this used mice so it’s not clear what those dose would be in humans).  Other mast cell active flavonols include quercetin, myricetin, rutin, fisein and kaempferol.

Quercetin downregulates the expression of histidine decarboxylase, the enzyme that modifies histidine, an amino acid, to histamine.  Quercetin also inhibits release of histamine, prostaglandins and leukotrienes.  Additionally, it decreases production and release of IL-1b, IL-6, IL-8 and TNF.  Quercetin was reported to be stronger and more effective at inhibiting mediator release than cromolyn when taken prophylactically, although this has not yet been judged as true by any regulatory body.  Quercetin is found naturally in a number of foods, such as red onion, sweet potato, kale, and many others.  It is also found in small quantities in teas made with Camellia sinensis.  Rutin is a derivative of quercetin, found in citrus fruits, apples, cranberries and others.

Fisetin, kaempferol, myricetin, quercetin and rutin inhibited IgE mediated histamine release and prevented increased concentration of calcium inside mast cells, which is necessary for degranulation.  Fisetin, quercetin and rutin all decreased production of IL-1b, IL-6, IL-8 and TNF. Fisetin, myricetin and rutin all decreased action of NF-kB, which controls the pathway regulating production of cytokines. Myricetin is a particularly effective mast cell stabilizer.  It decreased degranulation and release of TNF and IL-6, but not IL-1b or IL-8.

Flavonols have been evaluated for other medicinal properties aside from mast cell modulation.  Myricetin has been suggested as a treatment for many diseases, including diabetes, while kaempferol affects many molecular pathways, including estrogen signaling.  These molecules occur naturally in a number of plants, including walnuts, onions and red grapes for myricetin; apples, onions, persimmons, strawberries and cucumbers for fisetin; and potatoes, squash, cucumbers, peaches and Aloe vera for kaempferol.

 

References:

Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Weng Z., et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity inhumans. PLoS One. 2012; 7(3): e33805.

Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.

Lee, YS, et al. Homoisoflavonone prevents mast cell activation and allergic responses by inhibition of Syk signaling pathway. Allergy 2014; 69: 453-462.