The MastAttack 107: The Layperson’s Guide to Understanding Mast Cell Diseases, Part 11

I have answered the 107 questions I have been asked most in the last four years. No jargon. No terminology. Just answers.

19. How do other conditions affect mast cell disease?
Mast cell activity can affect literally every system in the body.
• Mast cells are found throughout the body and live in many tissues and organs in significant numbers.
• There are essentially three types of damaging mast cell activity:
Normal mast cells are getting bad signals from other cells and they do bad things. This is not mast cell disease because these mast cells are not broken. They are getting signals from other broken cells.
Abnormal mast cells do bad things and tell other nearby cells to do bad things. This is mast cell disease, specifically mast cell activation syndrome and sometimes monoclonal mast cell activation syndrome.
You make way too many mast cells, they are abnormal, they do bad things, and they tell other nearby cells to do bad things. This is mast cell disease, specifically all forms of mastocytosis (systemic, cutaneous, and mast cell leukemia), sometimes monoclonal mast cell activation syndrome and mast cell tumors (mastocytoma and mast cell sarcoma).
• Generally speaking, if you have mast cell disease, any other condition you have will irritate your mast cell disease. This can also work the other way around and mast cell disease can irritate your other conditions.
• Many conditions naturally trigger higher level mast cell activation.
• Any disease that causes your body to make a lot of cells very quickly is likely to trigger to mast cell activation. Cancers are mast cell activating. Non cancerous diseases where you make too many blood cells at once, like polycythemia vera or essential thrombocythemia, are are mast cell activating.
• Mast cells are usually found very close to tumors. Sometimes, they are found inside tumors. Mast cells are important for tumors to survive because they can make blood vessels to bring tumors the blood they need.
Diseases affecting the immune system are triggering to mast cells. In fact, many patients have mast cell activation syndrome caused by the immune disease irritating their mast cells so much. Many mast cell patients have autoimmune diseases like lupus or rheumatoid arthritis. Many patients also have deficiencies in their immune system. Because mast cells are immune cells, they are very responsive to signals from other immune cells. Mast cells think those cells need help from them to fight an infection or disease so they respond strongly to “help”.
Diseases that cause inflammation also trigger mast cells. This can happen whether the inflammation is local or not. Systemic inflammation is more irritating to mast cells since that kind of inflammation can find more mast cells throughout the body. Local inflammation can irritate mast cells nearby. It can also call mast cells from other parts of the body to that location.
• Mast cells are actively involved in fighting infections from viruses, bacteria, fungi, and parasites. This is the reason many mast cell patients find they are more reactive when they have even a minor illness, like a cold.
Any type of physical stress can activate mast cells. This can be something as simple as exercise or something more traumatic such as a car accident, a surgery, or childbirth. Even things that should be easy to recover from can activate mast cells, like a small cut, dehydration, or getting overheated. This also includes stress caused by another disease.
Emotional stress can activate mast cells, even if the big emotion is joy.
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Symptoms and effects of mast cell disease

 

The Provider Primer Series: Relevance of mast cells in common health scenarios

 

Symptom Cough
Role of mast cells Several mast cell mediators contribute to airway inflammation and subsequent symptoms including cough:

•             Histamine promotes bronchoconstriction, excessive production of mucus, and airway edema.[i]

•             Prostaglandin D2 promotes bronchoconstriction, mucus production, and airway edema.[i]

•             Leukotrienes C4 and D4 and chymase also contribute to mucus production and airway edema.[i]

•             Tryptase promotes overall increased reactivity of the airway.[i]

Chronic airway inflammation, as in asthma, is sometimes associated with increased mast cell population in pulmonary tissues.[i]

Mast cells remain activated in inflamed airways.[i]

Impact of condition on mast cells Mast cell activation can occur as a result of the physical stimuli such as coughing[ii].

Pain can trigger mast cell activation[iii].

Notes regarding condition treatment Dextromethorphan can trigger mast cell degranulation[iv].

Codeine and derivatives can trigger mast cell degranulation[v].

Beta-2 adrenergic agonists, inhaled and oral steroids, and inhaled cromolyn are frequently used in mast cell patients[vi].

Notes regarding mast cell treatment Antihistamines, leukotriene receptor antagonists, and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vii]

Racemic epinephrine can provide relief of pulmonary symptoms.[viii]

Special considerations for mast cell patients Chronic dry, unproductive cough sometimes occurs in mast cell patients.[ix]

Mast cell patients frequently have reactive airways.[ix]

Mast cells can produce and release prostaglandin E2, a mediator that participates in asthmatic inflammation and cough[x].

Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface[x].

 

Symptom Sore throat
Role of mast cells Pain can trigger mast cell activation.[iii]
Impact of condition on mast cells Mast cell driven nasal congestion can result in postnasal drip can irritate the throat.[ix]

Mast cell irritation of the throat can present similarly to infection by Streptococcus spp. or other pathogen. Cultures should be taken to properly evaluate for infection.[ix]

Viral, bacterial and fungal infection will activate mast cells through toll like receptors and through perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment Acetaminophen is recommended for pain relief in mast cell patients.[iv]
Notes regarding mast cell treatment Antihistamines and COX inhibitors are routinely taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Angioedema of the throat driven by mast cell disease is always a consideration in mast cell patients. If angioedema secondary to mast cell disease impinges upon airway, epinephrine and subsequent anaphylaxis treatments should be undertaken.[vii]

Oral allergy syndrome should be considered.[ix]

 

Symptom Rash
Role of mast cells Acute urticaria is usually driven by mast cell and basophil activation through IgE or non-IgE pathways.[xi]

Mast cell mediators histamine, leukotrienes and platelet activating factor contribute to itching.[xii]

Impact of condition on mast cells Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Non-mast cell driven conditions causing skin rashes can irritate mast cells in the skin.[xii]

Pain can trigger mast cell activation.[iii]

Notes regarding condition treatment Some -azole antifungals can induce mast cell degranulation.[xiv]
Notes regarding mast cell treatment Antihistamines and steroids, topical or systemic, and topical cromolyn can provide relief.[xii]
Special considerations for mast cell patients Mediator release by activated mast cells can produce systemic symptoms.[x]

In patients with a history of mast cell disease, mastocytosis in the skin should be considered.

o             Cutaneous mastocytosis accounts for approximately 90% of mastocytosis cases.[xii]

o             Cutaneous mastocytosis lesions demonstrate Darier’s sign, a wheal and flare reaction to touch.[xii]

o             A skin biopsy is necessary to confirm a diagnosis of cutaneous mastocytosis.[xii]

o             Patients with adult onset cutaneous mast cell lesions are usually later found to have systemic mastocytosis.[xii]

 

Symptom Fever
Role of mast cells Mast cells can produce prostaglandin E2.[x]

Mast cells can produce and release several pyrogens, including IL-1α, IL-1β, IL-6, IL-8, TNF, interferon-α, interferon-β, and interferon-γ.[x]

Impact of condition on mast cells Prostaglandin E2 can also downregulate or promote mast cell degranulation via binding at prostaglandin E2 receptors on mast cell surface.[x]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]
Special considerations for mast cell patients

 

Symptom Earache
Role of mast cells Mast cells are involved in the transmission of pain stimuli, including nerve pain.[iii]

Mast cells are involved in sensorineural hearing loss and tinnitus.[ix]

Impact of condition on mast cells Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment NSAIDS can trigger mast cell degranulation. Some mast cell patients are unable to take them.[xv]

Acetaminophen is generally recommended for use in mast cell patients.[iv]

Steroids (local and systemic) can stabilize mast cells.[vi]

Notes regarding mast cell treatment COX inhibitors are routinely taken by mast cell patients and may provide relief.[vi]

Antihistamines can provide relief for vestibular symptoms.[vi]

Special considerations for mast cell patients Hearing loss, tinnitus and hyperacusis sometimes occur in mast cell patients.[ix]

Sensorineural hearing loss of unknown origin has been documented in mast cell patients.[ix]

Some mast cell patients also have Ehlers Danlos Syndrome which can cause conductive hearing loss.[ix]

Mast cell disease can also cause auditory processing disorder.[ix]

Red ears are a common sign of mast cell activation. Sometimes, only one ear is affected.[ix]

 

Symptom Stomachache
Role of mast cells Mast cells are commonly found in the GI tract.[xvi]

Mast cell activation is involved in a number of GI conditions, including inflammatory bowel disease, ulcerative colitis and food allergies.[xvi]

Mast cell activation can cause chronic diarrhea, pseudoobstruction, obstruction, dysmotility, constipation, nausea, vomiting, and visceral GI pain.[xvi]

Impact of condition on mast cells GI inflammation can recruit mast cells to inflamed tissues.[xvi]

GI inflammation can trigger mast cell mediator release.[xvi]

Pain can trigger mast cell activation.[iii]

Viral, bacterial and fungal infection will activate mast cells via toll like receptors and perpetuated inflammatory signaling.[xiii]

Notes regarding condition treatment
Notes regarding mast cell treatment Histamine H2 blockers and PPIs are commonly taken by mast cell patients and can provide relief.[vi]
Special considerations for mast cell patients Mast cell patients can experience a wide array of severe GI symptoms with or without dense infiltration of GI tract by mast cells.[ix]

 

[i] Cruse G, Bradding P. (2016). Mast cells in airway diseases and interstitial lung disease. European Journal of Pharmacology 778, 125-138.

[ii] Zhang D, et al. (2012). Mast-cell degranulation induced by physical stimuli involves the activation of transient receptor-potential channel TRPV2. Physiol Res, 61(1):113-124.

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

[iv] Dewachter P, et al. (2014). Perioperative management of patients with mastocytosis. Anesthesiology, 120, 753-759.

[v] Brockow K, Bonadonna P. (2012). Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol, 12, 354-360.

[vi] Molderings GJ, et al. (2016). Pharmacological treatment options for mast cell activation disease. Naunyn-Schmiedeberg’s Arch Pharmol, 389:671.

[vii] Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

[viii] Walsh P, et al. (2008). Comparison of nebulized epinephrine to albuterol in bronchiolitis. Acad Emerg Med, 15(4):305-313.

[ix] Afrin LB. (2013). Diagnosis, presentation and management of mast cell activation syndrome. Mast cells.

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

[xi] Bernstein JA, et al. (2014). The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol, 133(5):1270-1277.

[xii] Hartmann K, et al. (2016). Cutaneous manifestations in patients with mastocytosis: consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma and Immunology; and the European Academy of Allergology and Clinical Immunology. Journal of Allergy and Clinical Immunology, 137(1):35-45.

[xiii] Sandig H, Bulfone-Paul S. (2012). TLR signaling in mast cells: common and unique features. Front Immunol, 3;185.

[xiv] Toyoguchi T, et al. (2000). Histamine release induced by antimicrobial agents and effects of antimicrobial agents on vancomycin-induced histamine release from rat peritoneal mast cells.  Pharm Pharmacol, 52(3), 327-331.

[xv] Grosman N. (2007). Comparison of the influence of NSAIDs with different COX-selectivity on histamine release from mast cells isolated from naïve and sensitized rats. International Immunopharmacology, 7(4), 532-540.

[xvi] Ramsay DB, et al. (2010). Mast cells in gastrointestinal disease. Gastroenterology & Hepatology, 6(12): 772-777.

 

Mast cell inhibitory effects of some microorganisms

We have talked recently about how infections can activate mast cells and result in worsening of symptoms in mast cell patients. However, some organisms are actually able to decrease mast cell degranulation and secretion of mediators. Some of these organisms are highly pathogenic with dangerous infectious capabilities, but some are commensal bacteria that can be found in probiotics. These findings support a growing body of evidence that indicates that the changes in our commensal organisms in the last thirty years have contributed to the increased frequency of atopic disease in developed countries. Additionally, improved hygiene and public health have decreased the frequency of some infections, which may also contribute to allergic conditions.

Lactobacillus and Bifidobacteria have been found to directly inhibit mast cell degranulation. Lactobacillus reduces both mast cell degranulation and cytokine secretion by reducing the number of IgE receptors on mast cell surface. Expression of IL-8 and TNF-a are actively decreased, while expression of the anti-inflammatory IL-10 is increased. Bifidobacterium bifidum inhibit IgE activation of mast cells in similar ways.

Salmonella typhimurium is a frequent cause of foodborne illness. In the US, it is estimated to cause 1,000,000 illness events annually, resulting in 19,000 hospitalizations and 380 deaths. It causes diarrhea, fever and severe abdominal cramping that can last several days. A 2001 study found that Salmonella are able to avoid detection by neutrophils through inactivation of local mast cells. Specifically, Salmonella inject a protein known as SptP into the fluid inside mast cells. Following exposure to Salmonella, mast cells lost their ability to degranulate, even when exposed to IgE or strong antigens.

Yersinia pestis, which causes plague, can also suppress mast cell degranulation by injecting a similar protein called YopH. Several forms of commensal E. coli (which do not cause infection) have been found to exhibit similar suppression.

Some organisms can cause mast cells to lyse (burst) and thus die. Pseudomonas aeruginosa releases exotoxin A, which causes lysis of mast cells.

Infectious fungi, such as Aspergillus fumigatus, release a gliotoxin that suppresses mast cell degranulation as well as mediator secretion. Other fungal products that decrease mast cell activity include FK-506 from Streptomyces tsukubaensis and cyclosporine A from Tolypocladium inflatum. Cyclosporine A is often used as an immunosuppressive after organ transplant and also sees some use in treating inflammatory disorders.

Some nematodes (roundworms) are also able to block mast cell degranulation. Filarial nematodes release a molecule, ES-62, that blocks IgE activation of mast cells as well as inhibiting secretion of allergic inflammatory factors. This finding is notable as it provides a possible reason why allergic diseases occur less frequently in developing countries. Toxoplasma gondii, a parasitic protozoan that causes toxoplasmosis, also prevented mast cell degranulation.

 

References:

Choi, H.W., Brooking-Dixon, R., Neupane, S., Lee, C.-J., Miao, E.A., Staats, H.F., Abraham, S.N., 2013. Salmonella typhimurium impedes innate immunity with a mast-cell-suppressing protein tyrosine phosphatase, SptP. Immunity 39,1108–1120.

Cornelis, G.R., 2002. Yersinia type III secretion: send in the effectors. J. Cell Biol. 158, 401–408.

Magerl, M., Lammel, V., Siebenhaar, F., Zuberbier, T., Metz, M., Maurer, M., 2008. Non-pathogenic commensal Escherichia coli bacteria can inhibit degranulation of mast cells. Exp. Dermatol. 17, 427–435.

Harata, G., He, F., Takahashi, K., Hosono, A., Kawase, M., Kubota, A., Hiramatsu, M.,Kaminogawa, S., 2010. Bifidobacterium suppresses IgE-mediated degranulationof rat basophilic leukemia (RBL-2H3) cells. Microbiol. Immunol. 54, 54–57.

Forsythe, P., Wang, B., Khambati, I., Kunze, W.A., 2012. Systemic effects of ingested Lactobacillus rhamnosus: inhibition of mast cell membrane potassium (IKCa)current and degranulation. PLoS One 7, e41234.

Oksaharju, A., Kankainen, M., Kekkonen, R.A., Lindstedt, K.A., Kovanen, P.T., Korpela,R., Miettinen, M., 2011. Probiotic Lactobacillus rhamnosus downregulates FCER1and HRH4 expression in human mast cells. World J. Gastroenterol. 17, 750–759.

Wesolowski, J., Paumet, F., 2011. The impact of bacterial infection on mast celldegranulation. Immunol. Res. 51, 215–226.

Niide, O., Suzuki, Y., Yoshimaru, T., Inoue, T., Takayama, T., Ra, C., 2006. Fungal metabolite gliotoxin blocks mast cell activation by a calcium- and superoxide-dependent mechanism: implications for immunosuppressive activities. Clin.Immunol. 118, 108–116.

Melendez, A.J., Harnett, M.M., Pushparaj, P.N., Wong, W.S., Tay, H.K., McSharry, C.P.,Harnett, W., 2007. Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat. Med. 13, 1375–1381.

Hae Woong Choi, Soman N. Abraham. Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms. Molecular Immunology 63 (2015) 74–79.

Allergic to infections: Other behaviors of toll like receptors

I posted earlier this week about Toll-like receptors (TLRs). These are receptors on the outside of mast cells (and other cells) that tell them there is an infection. Instead of only being able to bind very specific molecules like receptors often do, these TLRs are able to bind lots of molecules that look alike. Once these are bound, it tells mast cells to activate, make mediators and release them.

After TLR2, TLR4 is the most well understood Toll-like receptor. Molecules that bind TLR4 are from infectious gram negative bacteria, several viruses (including RSV), Cryptococcus neoformans, and Candida albicans. It also binds fibrinogen, which is involved in the clotting cascade, and nickel. When infected with a gram negative bacteria, like E. coli or Ps. aeruginosa, mast cells secrete inflammatory molecules TNF, IL-6, IL-13, and IL-1b.

TLR4 also has a very intriguing behavior with opioid receptors on mast cells. These opioid receptors are the binding sites for opiate medications, like morphine, which are common triggers for mast cell patients. One study found that treatment with morphine actually interferes with TLR4 making inflammatory molecules. Other studies have found that opiates can bind TLR-4 directly. When bound, TLR-4 signals for release of TNFa, CCL1 and IL-5.

Other TLRs on mast cells can be bound by various molecules and produce and release mediators in return. TLR3 is bound by viral proteins and induces release of interferon a and b; TLR5 binds proteins from some flagellated bacteria and releases TNF and IL-1b; TLR9 binds unmethylated DNA of the type released by bacteria and DNA viruses, and releases interferon a, TNF, IL-1b and leukotrienes.

All TLR receptors can function independently of IgE. This is one example of an IgE independent pathway, or a way mast cells can degranulate or secrete mediators without IgE.

 

References:

Hilary Sandig and Silvia Bulfone-Paus. TLR signaling in mast cells: common and unique features. Front Immunol. 2012; 3: 185.

Abraham S. N, St John A. L. (2010). Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 10440–452.

Dietrich N., Rohde M., Geffers R., Kroger A., Hauser H., Weiss S., Gekara N. O. (2010). Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Proc. Natl. Acad. Sci. U.S.A.1078748–8753

Gilfillan A. M., Tkaczyk C. (2006). Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol.6218–230.

Fehrenbach K., Port F., Grochowy G., Kalis C., Bessler W., Galanos C., Krystal G., Freudenberg M., Huber M. (2007). Stimulation of mast cells via FcvarepsilonR1 and TLR2: the type of ligand determines the outcome. Mol. Immunol. 442087–2094.

McCurdy,J.D., Olynych,T.J., Maher, L. H.,and Marshall, J.S.(2003). Cutting edge: distinct Toll-like receptor2 activators selectively induce different classes of mediator production from human mast cells. J. Immunol. 170, 1625–1629.

Medina-Tamayo, J., Ibarra-Sanchez, A., Padilla-Trejo,A., and Gonzalez- Espinosa, C. (2011). IgE-dependent sensitization increases responsiveness to LPS but does not modify development of endotoxin tolerance in mast cells. Inflamm. Res. 60, 19–27.

Qiao,H., Andrade,M.V., Lisboa,F. A., Morgan,K., and Beaven, M. A. (2006).FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells. Blood 107, 610–618.

Yoshioka,M., Fukuishi,N., Iriguchi,S., Ohsaki, K., Yamanobe,H., Inukai, A., Kurihara,D., Imajo,N., Yasui, Y., Matsui, N., Tsujita, T., Ishii, A., Seya,T., Takahama,M., and Akagi, M. (2007). Lipoteichoicacid down- regulates FcepsilonRI expressionon human mast cells through Toll-like receptor2. J. Allergy Clin. Immunol. 120, 452–461.

Varadaradjalou, S., Feger, F., Thieblemont, N., Hamouda, N.B., Pleau, J. M., Dy,M., and Arock, M. (2003). Toll-likereceptor2 (TLR2)and TLR4 differentially activate human mast cells. Eur. J. Immunol. 33, 899–906.