Master table of de novo mast cell mediators

 

Mediator Symptoms Pathophysiology
b-FGF (basic fibroblast growth factor) Angiogenesis, proliferation, wound healing, binds heparin
GM-CSF (granulocyte macrophage colony stimulating factor) Rheumatoid arthritis Induces stem cells to make granulocytes and monocycles
IL-1a Fever, insulin resistance, inflammatory pain Activates TNFa, stimulates production of PGE2, nitric oxide, IL-8 and other chemokines
IL-1b Pain, hypersensitivity Autoinflammatory syndromes, regulates cell proliferation, differentiation and death, induces COX2 activity to produce inflammatory molecules
IL-2 Itchiness, psoriasis Regulates T cell differentiation
IL-3 Drives differentiation of several cell types, including mast cells, and proliferation
IL-4 Airway inflammation, allergic asthma Regulates T cell differentiation
IL-5 Eosinophilic allergic disease Activates eosinophils, stimulates proliferation of B cells and antibody secretion, heavily involved in eosinophilic allergic disease
IL-6 Fever, acute phase inflammation, osteoporosis Inhibits TNFa and IL-1, stimulates bone resorption, reduces inflammation in muscle during exercise
IL-9 Asthma, bronchial hypersensitivity Increases cell proliferation and impedes apoptosis of hematopoietic cells
IL-10 Regulates the JAK-STAT pathway, interferes with production of interferons and TNFa.   Exercise increases levels of IL-10
IL-13 Airway disease, goblet cell metaplasia, oversecretion of mucus Induces IgE release from B cells, links allergic inflammation to non-immune cells
IL-16 Allergic asthma, rheumatoid arthritis, Crohn’s disease Attracts activated T cells to inflamed spaces,
IL-18 Linked to several autoimmune and inflammatory conditions, including Hashimoto’s thyroiditis Induces release of interferon-g, causes severe inflammatory reactions
Interferon-a Flu like symptoms, malaise, muscle soreness, fever, sore throat, nausea Inhibition of mast cell growth and activity
Interferon-b Flu like symptoms, malaise, muscle soreness, fever, sore throat, nausea Inhibition of mast cell growth and activity
Interferon-g Granuloma formation, chronic asthma Induces production of nitric oxide, IgG2a and IgG3 from B cells, increases production of histamine, airway reactivity and inflammation
Leukotriene B4 Mucus secretion, bronchoconstriction, vascular instability, pain Draws white cells to site of inflammation
Leukotriene C4 Mucus secretion, bronchoconstriction, vascular instability, pain Draws white cells to site of inflammation
MCP-1 Neuroinflammation, diseases of neuronal degeneration, glomerulonephritis Draws white blood cells to inflamed spaces,
MIF (macrophage migration inhibitory factor) Regulate acute immune response, release triggered by steroids
MIP-1a (macrophage inflammatory protein) Fibrosis Activates granulocytes, nduces release of IL-1, IL-6 and TNFa
Neurotrophin-3 Nerve growth factor
NGF (nerve growth factor) Regulates survival and growth of nerve cells, suppresses inflammation
Nitric oxide Bruising, hematoma formation, excessive bleeding Vasodilation, inhibition of platelet aggregation
PDGF (platelet derived growth factor) Platelet growth factor, growth of blood vessels, wound healing
Platelet activating factor Constriction of airway; urticaria; pain Platelet activation and aggregation, vasodilation
Prostaglandin D2 Flushing, mucus secretion, bronchoconstriction, vascular instability, mixed organic brain syndrome, nausea, abdominal pain, neuropsych symptoms, nerve pain Inflammation, pain, bronchoconstriction
Prostaglandin E2 Muscle contractions, cough Draws white blood cells to site of inflammation
RANTES (CCL5) Osteoarthritis Attracts white cells to inflamed spaces, causes proliferation of some white cells
SCF (stem cell factor) Regulates mast cell life cycle, induces histamine release
TGFb (transforming growth factor beta) Bronchial asthma, heart disease, lung fibrosis, telangiectasia, Marfan syndrome, vascular Ehlers syndrome syndrome Regulates vascular and connective tissues
TNFa (tumor necrosis factor) Fever, weight loss, fatigue Regulates death of cells and acute inflammation
VEGF (vascular endothelial growth factor) Bronchial asthma, diabetes Angiogenesis, draws white cells to inflamed spaces, vasodilation

 

 

Exercise and mast cell activity

Research on exercise induced bronchoconstriction represents a large body of work through which we can draw conclusions about mast cell behavior as affected by exercise.

Exercise has been found in a number of studies to induce mast cell degranulation and release of de novo (newly made) mediators. One study found that levels of histamine, tryptase and leukotrienes were increased following exercise in sputum of people with exercise induced bronchoconstriction. This same study found that in these patients, prostaglandin E2 and thromboxane B2 was decreased in sputum. Treating with montelukast and loratadine suppressed release of leukotrienes and histamine during exercise.

One important area of research is the interface between being asthmatic and being obese. Adipose tissue is known to release inflammatory molecules called adipokines. In particular, the adipokine leptin has been studied for its role in bronchoconstriction following exercise. Leptin (I did a previous post on leptin, which is also called the obesity hormone) enhances airway reactivity, airway inflammation and allergic response. It can also enhance leukotriene production. This last fact is interesting because obese asthmatics are less likely to respond to inhaled corticosteroids when compared to lean asthmatics, but both respond similarly to anti-leukotriene medications like montelukast.

LTE4 was found to be significantly higher in the urine of both obese and lean asthmatics following exercise. It was not increased in either obese non-asthmatics or healthy controls. Additionally, the level of LTE4 was significantly higher in obese asthmatics compared to lean asthmatics. In this same study, urinary 9a, 11b-PGF2 was elevated in both lean and obese asthmatics, but not in obese or healthy controls. The 9a, 11b-PGF2 level was also higher in obese asthmatics than lean asthmatics. The elevated LTE4 and 9a, 11b-PGF2 were found in urine testing rather than in sputum, indicating that these chemicals did not stay local to the lungs and airway.

It is thought that the high levels of leptin found in asthmatics drive the manufacture and release of leukotrienes and prostaglandins from mast cells, epithelial cells or eosinophils during exercise. Though the data are stacking up to look like this is the case, there has not yet been a definitive causal link established.

 

References:

Teal S. Hallstrand, Mark W. Moody, Mark M. Wurfel, Lawrence B. Schwartz, William R. Henderson, Jr., and Moira L. Aitken. Inflammatory Basis of Exercise-induced Bronchoconstriction. American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 6 (2005), pp. 679-686.

Hey-Sung Baek, et al. Leptin and urinary leukotriene E4 and 9α,11β-prostaglandin F2 release after exercise challenge. Volume 111, Issue 2, August 2013, Pages 112–117

 

Mast cell mediators: Prostaglandin D2 (PGD2)

Prostaglandin D2 (PGD2) is the predominant prostaglandin product released by mast cells. It is found prevalently in the central nervous system and peripheral tissues, where it performs both inflammatory and normal processes. In the brain, PGD2 helps to regulate sleep and pain perception. PGD2 can be further broken down into other prostaglandins, including PGF2a; 9a, 11b-PGF2a (a different shape of PGF2a), and forms of PGJ. 9a, 11b-PGF2a shares the same biological functions as PGD2. Both of these can be tested for in 24 hour urine test as markers of mast cell disease.

PGD2 is a strong bronchoconstrictor. It is 10.2x more potent in this capacity than histamine and 3.5x more potent than PGF2a. It has been associated with inflammatory and atopic conditions for many years. Presence of allergen activates PGD2 production in sensitized people. In asthmatics, bronchial samples can achieve over 150x the level of PGD2 compared to controls. Elevated PGD2 has been associated with chronic coughing.

PGD2 is a driver of inflammation in many settings. It acts on bronchial epithelium to cause production of chemokines and cytokines. It also brings lymphocytes and eosinophils to the airway, which induces airway inflammation and hyperreactivity in asthmatics. PGD2 may also inhibit eosinophil cell death, resulting in further inflammation.

An interesting facet of PGD2 is its role in nerve pain. It has been found that PGD2 is produced by microglia in the spine after a peripheral nerve injury. These cells make more COX-1, which then makes PGD2. Newer COX-2 inhibiting NSAIDs do not affect nerve pain in mouse models, but older NSAIDs that inhibit COX-1 and COX-2 reduce neuropathy.

PGD2 is found to inhibit inflammation in other settings. It can reduce eosinophilia in allergic inflammation in mouse models. Additionally, once the acute phase of inflammation is over and it is resolving, administering a COX-2 inhibitor actually makes the inflammation worse. This indicates that PGD2 may be important in resolving inflammation in some processes.

Aspirin is commonly used in mast cell patients to inhibit prostaglandin production. PGD2 is primarily manufactured by COX-2, but the pathway that evokes neuropathy uses COX-1. There are a number of COX-1 and COX-2 inhibitors available.

In mast cell patients, PGD2 is probably most well known for causing flushing. This happens due to dilation of blood vessels in the skin. Due to a well characterized response to aspirin, this is generally the first line medication choice. Some salicylate sensitive mast cell patients undergo aspirin desensitization to be able to use this medication.

 

References:

Emanuela Ricciotti, Garret A. FitzGerald. Prostaglandins and Inflammation. Arterioscler Thromb Vasc Biol. 2011; 31: 986-1000.

Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S. Prostaglandin D2 as a mediator of allergic asthma. Science. 2000;287: 2013–2017.

G Bochenek, E Nizankowska, A Gielicz, M Swierczynska, A Szczeklik. Plasma 9a,11b-PGF2, a PGD2 metabolite, as a sensitive marker of mast cell activation by allergen in bronchial asthma. Thorax 2004; 59: 459–464.

Victor Dishy, MD, Fang Liu, PhD, David L. Ebel, BS, RPh, George J. Atiee, MD, Jane Royalty, MD, Sandra Reilley, MD, John F. Paolini, MD, PhD, John A. Wagner, MD, PhD, and Eseng Lai, MD, PhD. Effects of Aspirin When Added to the Prostaglandin D2 Receptor Antagonist Laropiprant on Niacin-Induced Flushing Symptoms. Journal of Clinical Pharmacology, 2009; 49: 416-422

MCAS: Neurologic and psychiatric symptoms

The neuropsychiatric symptoms associated with MCAS are numerous and are results of the chemicals released by mast cells.

Headaches are a very common complaint. They can sometimes be managed with typical remedies (Excedrin, Tylenol) and antihistamine treatment often helps with this symptom quickly. However, in some patients, headaches can be disabling. Diagnosis of migraine is not unusual, with mast cell degranulation having been tied previously to migraines.

Dizziness, lightheadedness, weakness, vertigo, and the feeling of being about to faint are all typical in MCAS, though true fainting spells are less common than in mastocytosis. These symptoms often cause many MCAS patients to be diagnosed with dysautonomia or POTS.

MCAS patients often experience increased activation of sensory and motor nerves. This manifests as generic neurologic symptoms, sometimes several at once, like tingling, numbness, paresthesia and tics. Tics generally do not spread from the place they initially present. Paresthesias seem to progress for a period of time, then wane and disappear. Extremities are most commonly affected.

EMG and nerve conduction studies are typically normal or abnormal in a way that is not diagnostic. These tests sometimes reflect a possibility of chronic inflammatory demyelinating polyneuropathy (CIDP.) These patients also sometimes are positive for monoclonal gammopathy of unknown significance (MGUS), a blood marker that has been tied to multiple myeloma. However, in these patients, the MGUS is believed to be an effect of the MCAS.

Another subset of patients are diagnosed with subacute combined degeneration (SCD), a deterioration of the spinal cord associated with B12 deficiency. They are sometimes treated for pernicious anemia despite lack of hematologic support for this diagnosis.

Prostaglandin D2 is a known effector of nerve damage and has been blamed for many of the neurologic symptoms seen in MCAS. Astrogliosis, abnormal proliferation of astrocytes (nerve cells in the brain), and demyelination (loss of the insulating cover for nerves that allows the body to send signals) are markers of neurodegeneration. These factors cause scarring and inhibit nerve repair mechanisms. PGD2 is made by an enzyme called hematopoietic PGD synthase. In mice that don’t make this enzyme, these kinds of neuroinflammation are suppressed. Treatment of normal mice with an inhibitor of this enzyme (HQL-72) also decreases these actions. This indicates that PGD2 is critical in causing neuroinflammation including demyelination. PGD2 also activates pain receptors strongly, causing sometimes profound neurologic pain.

PGD2 is also the most potent somnagen known, meaning that it induces sleep more strongly than any other molecule. MCAS patients report inordinately deep sleep, “mast cell coma.” This is likely due to excessive PGD2. Conversely, some MCAS patients also have insomnia, from excessive histamine.

I have written at length before about cognitive and psychiatric manifestations of mastocytosis, which are the same as in MCAS. Cognitive and mood disturbances are all kinds are reported. Brain fog, including short term memory troubles and word finding problems, is the most common symptom. Irritability, anger, depression, bipolar affective disorder, ADD, anxiety, panic disorders and even sometimes frank psychosis can present. Such symptoms in mastocytosis patients were referred to as mixed organic brain syndrome, a term coined in 1986. The important aspect of these symptoms in MCAS is that they are caused by mast cell activation. As such, they are most effectively treated by managing mast cell release symptoms. Some patients do find relief in some psychiatric medications, but the psychiatrist should be aware that these symptoms are part of mast cell pathology.

Additionally, PTSD is not rare in MCAS patients. This is most often due to the trauma from negative interactions with the medical industry.

Autism is significantly increased in patients with mastocytosis. Similar findings are beginning to surface with MCAS patients. Interesting, most autism spectrum disorder patients have food intolerance and general allergic symptoms. A future post will discuss this in more detail.

References:

Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome. 2013. Mast cells.

Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011;4:10-17.

Ikuko Mohri, Masako Taniike, Hidetoshi Taniguchi, Takahisa Kanekiyo, Kosuke Aritake, Takashi Inui, Noriko Fukumoto, Naomi Eguchi, Atsuko Kushi, Hitoshi. Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in twitcher. The Journal of Neuroscience, April 19, 2006 • 26(16):4383– 4393.

Rogers MP, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med. 1986 Jul-Aug;48(6):437-47.