|Receptor||Ligand (molecules that bind to the receptor)||Result|
|Nicotinic acetylcholine receptor||Acetylcholine||Increases severity of anaphylaxis|
|NOD1, NOD2||Bacterial products||Cytokines; dependent upon ligand|
|Paired Ig-like receptor B (PIR-B)||Inhibitory|
|Peripheral benzodiazepine receptor||Benzodiazepines||Inhibits mediator release|
|Platelet endothelial cell adhesion molecule (PECAM-1)||Inhibitory|
|Progesterone receptor||Progesterone||Inhibits mediator release|
|Prostaglandin E receptors, EP2,||Prostaglandin E||Downregulates IgE mediated response, inhibits prostaglandin and leukotriene production
|Prostaglandin E receptors, EP3, EP4||Prostaglandin E||Increases IgE mediated degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
Increases IgE dependent cytokine production
|Protease activated receptors 1-4 (PAR1-4)||Serine proteases (trypsin, tryptase, chymase)||Histamine release, mast cell activation|
|Purinoreceptor P2Y11||ATP||Production of prostaglandins and leukotrienes|
|Purinoreceptor P2Y2||ATP, UTP||Production of prostaglandins and leukotrienes|
|Purinoreceptors P2Y1, P2Y12, P2Y13||ADP||Production of prostaglandins and leukotrienes|
|Sialic acid binding||Inhibitory|
|Sphingosine-1-phosphate S1P2||Sphingosine-1-phosphate||Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
|TGFb receptor 1||TGFb||Decreases IgE dependent degranulation, IgE dependent TNF production|
|TLR1-9||Bacterial and viral products||Cytokines ; dependent upon ligand|
|Urokinase receptor||Urokinase||Movement of mast cells|
|Vitamin D receptor||Vitamin D||Mast cell development|
|β2-adrenoreceptor||Adrenaline||Inhibits FcεRI degranulation and cytokine production and secretion|
|Receptor||Ligand (molecules that bind to the receptor)||Result|
|Gp49B1||Gp49B1-αvβ3||Inhibits IgE activation|
|GPCR mimetic MRGX2||Mastoparan, cortistatin, PAMP-12, somatostatin, neuropeptide FF, oxytocin, substance P||Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin|
|GPR34||Lysophosphatidylserine, b defensins, LL-37??||Enhances degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin
PGD2, PGE2, LTC4, IL-2, IL03, IL-5, IL-1b, TNF, IL-31, GM-CSF, IL-5, TNFg
|GPR92||Lysophosphatidic acid||Cytokine production and release|
|IL-10 receptor||IL-10||Decreases IgE dependent release of IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5|
|IL-3 receptor||IL-3||Increases IgE dependent release of histamine and leukotriene C4|
|IL-4 receptor||IL-4||Increases IgE dependent release of histamine, leukotriene C4 and IL-5 release|
|IL-5 receptor||IL-5||Increases IgE dependent secretion :
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
|Cysteinyl Leukotriene receptor 1, 2||Leukotrienes||Cytokine production and proliferation|
|LPA1, LPA3||Lysophosphatidic acid||Encourage development|
|Mast cell function associated antigen (MAFA)||Inhibitory|
|MHC I||Antigenic peptides||For activating other immune cells|
|MHC II||Antigenic peptides||For activating other immune cells|
|MRGX2||Mastoparan, somatostatin, substance P, platelet factor 4, mellitin
|Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin
De novo: IL-3, IL-8, TNFa, GM-CSF
|Myeloid associated Ig-like receptor 1||Unknown||Inhibition of mast cell activation and mediator release|
|Neurokinin receptors: NK1R, NK2R, NK3R, VPAC2||Substance P, CGRP, hemokinin A, VIP, nerve growth factor, neuropeptide Y||Substance P: Degranulation:
Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin
Produce and release cytokines
VIP, Neuropeptide Y: induce release of histamine
Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin
|Neurotrophin receptor TrkA||NGF||Degranulation: histamine, serotonin, NGF|
|Neurotrophin receptor TrkB||BDNF, NT-4||No degranulation|
|Neurotrophin receptor TrkC||Neurotrophin 3||No degranulation|
Aneurysms are formed when elastic tissue is degraded by proteases and MMPs; the vessel is thinned due to smooth muscle loss; and the endothelium is broken down, resulting in inflammation. There is a significant body of evidence linking aneurysm formation and growth to mast cell activity.
A number of studies have found that mast cells are present in larger numbers in vasculature near aneurysms. Mast cells are increased in cerebral arteries of patients who died from subarachnoid hemorrhage. In particular, mast cell number is higher in arteries close to the rupture site. Mast cell count has been linked previously to aneurysm instability. Another study found that activated mast cells were increased in the aortas of patients who died from abdominal aortic aneurysms. Increased mast cells are also found in ascending aortic aneurysms. Mast cell density is a predictor for occurrence of ascending aortic aneurysm.
Chymase activity has been heavily implicated in aneurysm physiology. One study found that levels of angiotensin II were unlikely to induce development of aneurysm, but that degradation of the vessel by chymase may weaken the aneurysm and increase risk of rupture. Increased chymase activity was found in an additional fourteen patients having aortic aneurysms repaired. In thoracic aortic aneurysm patients, chymase positive mast cells were found in inflamed areas. Chymase may participate in the generation of reactive oxygen species. In abdominal aortic aneurysm samples, most players in the renin-angiotensin system, including chymase and cathepsins, are increased.
Serpin A3, a protease inhibitor, normally regulates activity of elastase, chymase and cathepsin G. It is thought that deficiency of this molecule may worsen damage caused by chymase.
Mast cell proteases, like tryptase and chymase, may be involved in the formation of aneurysms. Erosion of the endothelium occurred in the thrombosed region of the vessel, followed by decreased oxygen supply to the underlying vessel. Tryptase and chymase may participate in rupture of the vessel and intravascular hemorrhage. Adrenomedullin, a mast cell mediator, is found to be strongly expressed in mast cells to local to aneurysms. Adrenomedullin suppresses formation of the extracellular matrix.
Serum tryptase levels in abdominal aortic aneurysms correlated well with growth of aneurysm as well as risk of complications during repair. Tryptase deficient mice were completely protected against developing this type of aneurysm. Tryptase deficiency reduced expression of cathepsins, as well as activation of endothelial cells and movement of monocytes. Tryptase induces release of cathepsins that trigger apoptosis, so this may be a mechanism.
5-lipoxygenase is the enzyme that drives leukotriene formation. Mice deficient in this molecule were protected against aneurysm formation. They also had less inflammation and apoptosis, lower IL-6 and IFN-γ. Mast cell degranulation augmented aneurysm formation while mast cell stabilizer cromolyn decreased it. Another study found that treatment with tranilast, another mast cell stabilizer, decreased the diameter of the aorta.
Leukotriene C4 and 5-lipoxygenase are increased in patients with abdominal aortic aneurysms, but leukotriene B4 is not. Leukotrienes increase release of MMPs and encourage matrix degradation. Leukotrienes may be a therapeutic target to slow aneurysm progression.
Kennedy, Simon, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53-65.
Bot, Ilze, et al. Mast cells: Pivotal players in cardiovascular diseases. Current Cardiology Reviews, 2008, 4, 170-178.
One of the most well described non-allergic functions of the mast cell is wound healing. Mast cells are involved in many functions integral to remodeling and closing wounds.
Immediately following formation of a wound, signals are sent to constrict vessels near the injury to decrease the risk of bleeding and infection. After bleeding has been minimized, the blood vessels become a little more permeable to let cells and molecules from the bloodstream into the injured area in order to promote healing and prevent infection. These actions activate the complement clotting system, which produces molecules C3a and C5a. These molecules bind to mast cells and induce degranulation.
Following degranulation, vessels become more permeable through the action of histamine and other mediators. Fibrinogen, important in clot formation, leaves the blood stream and accumulates in the tissue. This triggers thrombin to change fibrinogen to fibrin, forming a clot. Mast cells are active in preventing excessive clotting. Tryptase and heparin are released from granules bound together, and this complex degrades fibrogen and inactivates thrombin.
The extracellular matrix is the structures which give substance to groups of cells and vessels. Following wound formation, fibronectin and type III collagen molecules gather near the injury. Mast cell proteases chymase and tryptase break down the extracellular matrix molecules to make room for newly made cells to close the wound. It is also possible that mast cell mediator CMA1 breaks down fibronectin.
Granulation tissue forms when wounds are healing. Granulation involves several activities, such as cell proliferation, develop of blood vessels, and building of new skin. Fibroblasts, which make collagen and extracellular matrix molecules, are drawn to the injury by mast cell signaling. Once there, they are induced to proliferate by action of the presence of histamine, tryptase, heparin and fibroblast growth factor. Mast cell degranulation also drives generation of new blood vessels through action of histamine, heparin, chymase, fibroblast growth factor, VEGF and tumor necrosis factor. Formation and proliferation of new epithelial tissue is also encouraged by TGF-b1, histamine, IL-1a, IL-1b, IL-6, tryptase, and heparin.
Once enough new cells have been made, the fibroblasts become myofibroblasts to make new muscle. Histamine and tryptase mediate this step. The fibroblasts directly interact with mast cells. Mast cell proteases tryptase and chymase trigger the activation of several molecules that mediate remodeling of the extracellular matrix. The wound is closed following this remodeling and laying down of new skin.
Douaiher, Jeffrey, et al. Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing Advances in Immunology, Volume 122 (2014): Chapter 6.
Christine Möller Westerberg, Erik Ullerås, Gunnar Nilsson. Differentiation of mast cell subpopulations from mouse embryonic stem cells. Journal of Immunological Methods 382 (2012) 160–166.
|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|
|Angiogenin||Tissue damage||Formation of new blood vessels, degradation of basement membrane and local matrix|
|Arylsulfatases||Breaks down molecules to produce building blocks for nerve and muscle cells|
|Bradykinin||Angioedema, swelling of airway, swelling of GI tract, inflammation, pain, hypotension||Vasodilation, induces release of nitric oxide and prostacyclin|
|Carboxypeptidase A||Muscle damage||Tissue remodeling|
|Cathepsin G||Pain, muscle damage||Converts angiotensin I to II, activates TGF-b, muscle damage, pain, fibrosis, activates platelets, vasodilation|
|Chondroitin sulfate||Cartilage synthesis|
|Chymase||Cardiac arrhythmia, hypertension, myocardial infarction||Tissue remodeling, conversion of angiotensin I to II, cleaves lipoproteins, activates TGF-b, tissue damage, pain, fibrosis|
|Corticotropin-releasing hormone||Dysregulation has wide reaching and severe effects||Stimulates secretion of ACTH to form cortisol and steroids|
|Endothelin||Hypertension, cardiac hypertrophy, type II diabetes, Hirschsprung disease||Vasoconstriction|
|Eotaxin (CCL11)||Cognitive deficits||Attracts eosinophils, decreases nerve growth|
|Heparin||Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers||Cofactor for nerve growth factor, anticoagulant, prevents platelet aggregation, angiogenesis|
|Histamine||Headache, hypotension, pruritis, urticaria, angioedema, diarrhea, anaphylaxis||Vasodilation of vessels, vasoconstriction of atherosclerotic coronary arteries, action of endothelium, formation of new blood vessels cell proliferation, pain|
|Hyaluronic acid||Degradation contributes to skin damage||Tissue repair, cartilage synthesis, activation of white blood cells|
|IL-8 (CXCL8)||Mast cell degranulation||Attracts white blood cells (mostly neutrophils) to site of infection, activates mast cells, promotes degranulation|
|Kininogenases||Angioedema, pain, low blood pressure||Synthesis of bradykinin|
|Leptin||Obesity||Regulates food intake|
|Matrix metalloproteinases||Irregular menses (MMP-2)||Tissue damage, modification of cytokines and chemokines (modifies molecules to make them useful)|
|MCP-1 (CCL2)||Nerve pain||Attracts white blood cells to site of injury or infection, neuroinflammation, infiltration of monocytes (seen in some autoimmune diseases)|
|MCP-3 (CCL7)||Increases activity of white blood cells in inflamed spaces|
|MCP-4 (CCL13)||Shortness of breath, tightness of airway, cough||Attracts white blood cells to inflamed spaces, induces mast cell release of TNFa and IL-1, asthma symptoms|
|Phospholipase A2||Vascular inflammation, acute coronary syndrome||Generates precursor molecule for prostaglandins and leukotrienes|
|RANTES (CCL5)||Osteoarthritis||Attracts white cells to inflamed spaces, causes proliferation of some white cells|
|Renin||Cardiac arrhythmias, myocardial infarction, blood pressure abnormalities||Angiotensin synthesis, controls volume of blood plasma,lymph and interstitial fluid, regulates blood pressure|
|Serotonin/5-HT||Nausea, vomiting, diarrhea, headache, GI pain||Vasoconstriction, pain|
|Somatostatin||Low stomach acid symptoms, low blood sugar||Regulates endocrine system, cell growth and nerve signals, inhibits release of glucagon and insulin, decreases release of gastrin, secretin and histamine|
|Substance P||Neurologic pain, inflammation, nausea, vomiting, mood disorders, anxiety||Transmits sensory nerve signals, including pain, mood disorders, stress perception, nerve growth and respiration|
|Tissue plasminogen activator||Blood clots||Activates plasminogen, clotting|
|Tryptase||Hematoma formation, bruising, prolonged bleeding post-biopsy, gum bleeding, epistaxis, GI bleed, conjunctival bleeding, bleeding ulcers; inflammation||Activation of endothelium, triggers smooth muscle proliferation, activates degradation of fibrinogen, activates MMP molecules,tissue damage, activation of PAR, inflammation, pain|
|Urocortin||Increased appetite when stressed, inflammation, low blood pressure||Vasodilation, increases coronary blood flow|
|Vasoactive intestinal peptide||Decreased absorption, low blood pressure, low stomach acid symptoms||Vasodilation, mast cell activation, lowers blood pressure, relaxes muscles of trachea, stomach and gall bladder, inhibits gastric acid secretion, inhibits absorption|
|VEGF||Diseases of blood vessels||Formation of new blood vessels, vasodilation and permeability of smaller vessels|
Chymase is a mediator produced and released by mast cells. It is an enzyme that converts angiotensin I to angiotensin II, which is important in regulating blood pressure. Chymase can also activate TGF-b1, IL-1b and degrade some of the proteins that hold cells together in tissues.
Release of chymase by local mast cells is a large factor in plaque instability. This is thought to be by raising amount of angiotensin II and degrading a structure that stabilizes the plaque. Chymase also causes apoptosis, or cell death, of smooth muscle cells, which lie underneath the plaque. It was recently discovered that activation of the toll like receptor 4 (TLR4) on the surface of the mast cell causes the mast cell to release IL-6. IL-6 then binds to the mast cell and causes it to make and release chymase.
Chymase and tryptase also interfere with cholesterol transport. In plaques, macrophages eat cholesterol and become foam cells. When the foam cells try to release the cholesterol, chymase and tryptase can prevent this, which stabilizes the plaque and makes it larger.
Mast cell activation is also known to affect plaque behavior. In mast cells that could not be activated by IgE, the size of the plaque and cell death around it were reduced. IgE levels are higher in patients who suffer acute coronary syndromes compared with those who don’t, with IgE levels peaking seven days after the event. Patients with hyper-IgE syndrome are much more likely to have coronary artery dilation or aneurysm, although atherosclerosis was not common. A whole body MRI detected impaired vascular integrity in these patients. These patients are expected to be more prone to mast cell activation.
In mastocytosis patients, no increase in atherosclerosis has been reported, though cardiovascular symptoms are not unusual. Some mastocytosis patients demonstrate vascular instability. Two cases of strokes due to cranial artery dissection have been published.
Mice that lack substance P, a neuropeptide that activates mast cells, have better cardiac function than expected. In mouse models, adding substance P to a plaque could cause hemorrhage only if the mouse had mast cells. This indicates that mast cell activation is important in plaque rupture.
Simon Kennedy, Junxi Wu, Roger M. Wadsworth, Catherine E. Lawrence, Pasquale Maffia. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53–65.
Ramalho, L. S., Oliveira, L. F., Cavellani, C. L., Ferraz, M. L., de Oliveira, F. A., Miranda Corrêa, R. R., et al. (2012). Role of mast cell chymase and tryptase in the progression of atherosclerosis: study in 44 autopsied cases. Ann Diagn Pathol 17, 28–31.
Meléndez, G. C., Li, J., Law, B. A., Janicki, J. S., Supowit, S. C., & Levick, S. P. (2011). Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc Res 92, 420–429.
Guo, T., Chen,W. Q., Zhang, C., Zhao, Y. X., & Zhang, Y. (2009). Chymase activity is closely related with plaque vulnerability in a hamster model of atherosclerosis. Atherosclerosis 207, 59–67.
PAF is released by many different cells, including eosinophils, mast cells, neutrophils, monocytes, macrophages and endothelial cells. PAF receptors are expressed by platelets, monocytes, mast cells, neutrophils, and eosinophils. T and B cells do not express PAF receptors, but PAF can stimulate them to migration of these cells. PAF receptors are found to be increased in eosinophils of asthma patients. PAF receptors are also elevated in lungs of asthmatic patients. PAF can activate mast cells and basophils, causing histamine release. One study proposed the PAF activation of basophils may play a role in aspirin sensitivity in asthma patients.
PAF is most well known for its effects on the airway. It causes constriction of the airway and can affect the way oxygen is brought into the lungs. However, it also has many other effects in the body, many of which affect anaphylaxis and severity thereof.
PAF activates eosinophils and neutrophils to degranulate. It also causes leukotriene C4 production by activated eosinophils in asthma patients, but not in normal patients. A PAF inhibitor has been observed to prevent eosinophil migration and leukotriene C4. Another PAF inhibitor was able to inhibit eosinophil activation by PAF. In activated neutrophils in asthma patients, PAF causes an increase in secretion of leukotriene B4 and increased 5-lipoxygenase activity.
PAF is a powerful signal for eosinophils to migrate toward the cell releasing PAF, and may be involved in inflammation resulting in eosinophilic infiltration. PAF can cause eosinophilic movement across endothelium and into airway. This behavior is increased during asthma attacks and can be minimized with steroids.
PAF injected into the skin causes a biphasic reaction with immediate hiving, then a delayed redness and pain reaction that causes eosinophilic infiltration. PAF also increases IL-6 production by macrophages, activates IL-4 production by T cells, and enhances IL-6 production by mononuclear cells in peripheral blood.
PAF has been heavily linked to asthma. One study found higher levels of PAF as well as lower level of the enzyme that inactivates PAF in plasma of asthmatic adults both during attacks and the rest of the time. When exposed to allergens, PAF level in blood rapidly increases. The large increases in PAF level upon exposure were ameliorated upon successful allergen immunotherapy (also known in the US as “allergy shots”).
PAF induced bronchoconstriction does not affect histamine release and is not alleviated by H1 receptor antihistamines. Inhaling PAF does not change plasma histamine level in asthmatics. Leukotrienes may behave as secondary mediators of PAF action. Zileuton attenuated systemic and respiratory effects of PAF, including airway constriction and changes in neutrophil behavior.
PAF level, and the level of the enzyme that metabolizes it, PAF-acetylhydrolase, is directly correlated to severity of anaphylaxis. Patients with grade I anaphylaxis have 2.5x as much PAF as controls; grade II, 5x; and grade III, 10x. PAF blockers are being investigated for use in this context. Rupatadine is available in some countries, and has H1 antihistamine and PAF blocking activity.
The exact nature of PAF’s activity in anaphylaxis is unclear. It has been shown to cause mast cell degranulation and increased production and release of prostaglandin D2. It can also amplify the response to IgE, making the allergic reaction worse. However, these effects were not seen in skin mast cells for unknown reasons. The source of PAF that acts on mast cells in anaphylaxis is unknown, but is thought to be at least partially from mast cells themselves.
Kasperska-Zajac, Z. Brzoza, and B. Rogala. Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma. Inflammation, Vol. 31, No. 2, April 2008.
Peter Vadas, M.D., Ph.D., Milton Gold, M.D., Boris Perelman, Ph.D., Gary M. Liss, M.D., Gideon Lack, M.D., Thomas Blyth, M.D., F. Estelle R. Simons, M.D., Keith J. Simons, Ph.D., Dan Cass, M.D., and Jupiter Yeung, Ph.D. Platelet-Activating Factor, PAF Acetylhydrolase, and Severe Anaphylaxis. N Engl J Med 2008; 358:28-35.
Vadas P, Gold M, Liss G, Smith C, Yeung J, Perelman B. PAF acetylhydrolase predisposes to fatal anaphylaxis. J Allergy Clin Immunol 2003;111: S206-S206.
Kajiwara N, Sasaki T, Bradding P, Cruse G, Sagara H, Ohmori K, Saito H, Ra C, Okayama Y. Activation of human mast cells through the platelet-activating factor receptor. J Allergy Clin Immunol. 2010 May; 125(5): 1137-1145.
Eosinophils are granulocytes that can localize to the tissues under certain conditions, including allergic response. Eosinophilic granules contain the positively charged proteins major basic protein, eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin. Like mast cells, eosinophils release these granules in response to many things, including inflammatory signals, parasitic infection, tissue damage and allergic inflammation. They express many receptors, including receptors for platelet activating factor (PAF) and histamine receptors. PAF and histamine are both released by mast cells.
Mast cells and eosinophils are overwhelmingly found together in late and chronic stages of allergic inflammation. They function in such close concert that mast cells, eosinophils and their effects have been termed the allergic effector unit (AEU). Mast cells release signals that affect eosinophil behavior and receive signals from eosinophils. These cells often also function while in physical contact with one another. When eosinophils are in physical contact with mast cells, they live longer than normal. CD48, 2B4, DNAM-1 and Nectin-2 are all involved in the mast cell – eosinophil contact mechanism.
Major basic protein can activate mast cells and eosinophil peroxidase is taken up by mast cells as a signaling molecule. Tryptase draws eosinophils to mast cells and causes release of eosinophil peroxidase, IL-6 and IL-18 from eosinophils. Histamine and prostaglandin D2 also signal eosinophils to migrate towards mast cells. Mast cell secreted eotaxin activates eosinophils by the histamine 4 (H4) receptor. Both cell types secrete leukotrienes and both express leukotriene receptors.
When grown together, researchers are able to investigate the behavior of mast cells and eosinophils together. This is called co-culture. In 29% of cases, eosinophils will migrate towards resting (non-activated) mast cells. In 45% of cases, eosinophils will migrate towards IgE activated mast cells. In 47% of cases, eosinophils will migrate towards mast cells activated through a non-IgE pathway. The specific attractant signal has not been identified.
When co-cultured with eosinophils, basal mast cell mediator release was 5% higher. When the mast cells were activated by IgE, degranulation was 15% higher. In order to activate mast cells, eosinophils must be in contact with them. However, mast cells can activate eosinophils without contact. In co-cultures with mast cells, eosinophil peroxidase constituted 47% of eosinophil released proteins, compared with 18% normally.
In low term co-cultures, both mast cells and eosinophils stayed activated. TNF was high in the co-culture, but not IL-6, IL-8 and IL-10. Importantly, low relative numbers of mast cells could activate eosinophils, but mast cell activation was most effective when eosinophils were more numerous. Eosinophils are thought to reduce the threshold of mast cell responsiveness to IgE.
Elishmereni M, Bachelet I, Nissim Ben Efraim AH, Mankuta D, Levi-Schaffer F. Interacting mast cells and eosinophils acquire an enhanced activation state in vitro. Allergy 2013; 68: 171–179.
Elishmereni M, Alenius HT, Bradding P, Mizrahi S, Shikotra A, Minai-Fleminger Y, et al. Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro. Allergy 2011;66:376–385.
Minai-Fleminger Y, Elishmereni M, Vita F, Soranzo MR, Mankuta D, Zabucchi G et al. Ultrastructural evidence for human mast cell-eosinophil interactions in vitro. Cell Tissue Res 2010;341:405–415.
Puxeddu I, Ribatti D, Crivellato E, Levi- Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol 2005;116:531–536.
Sphingosine-1-phosphate (S1P) is a lipid mediator involved in many processes, including development of vessels, vascular permeability, and immune function. It is found in the blood, often bound with proteins such as high density lipoprotein (HDL, “good cholesterol”). Receptors for S1P are found on many cell types.
Activation of the high affinity receptor for IgE causes production of S1P by mast cells. This may also affect the expression and activation of S1P receptors. Mast cells then secrete S1P into the surrounding space. Mast cells also have receptors to bind S1P.
The S1P1 receptor helps to direct mast cells to sites of inflammation, but does not influence degranulation. The S1P2 receptor deters from localizing to sites of inflammation but enhances degranulation once they have migrated. S1P is known to increase during acute tissue inflammation, in airways following asthmatic challenge and in joints of rheumatic patients. S1P may be responsible for the accumulation of immune cells in such places, but the exact nature of this role is unclear.
S1P receptors regulate the vascular system, including heart rate and permeability. S1P2 receptor makes vessels more permeable and regulates blood flow to various organs. S1P2 receptor is involved in counteracting the vasodilation effect of histamine (and thus low blood pressure). Histamine can stimulate S1P production.
S1P can also cause bradycardia and high blood pressure via the S1P3 receptor. I am curious to know if S1P is involved in the high blood pressure type of anaphylaxis some people have.
In models where the genes for making S1P have been deleted, recovery from anaphylaxis is delayed, with severe hypotension. However, in mice with S1P2 receptors, injecting S1P could rescue mice from anaphylaxis. For this reason, molecules that can act on the S1P receptors are being investigated as possible drug targets to produce an alternative to epinephrine.
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Olivera A, Eisner C, Kitamura Y, et al. Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock. J Clin Invest. 2010 “in press”.