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Mast Cells and Anaphylaxis

  • Anaphylaxis and Drug Allergy (DA Khan and M Castells, Section Editors)
  • Published:
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Abstract

For half a century, it has been known that the mast cell is the cell responsible for the majority of anaphylactic events. Its mediators, taken as a whole, are capable of producing all of the clinical manifestations of these events. With the discovery of immunoglobulin E (IgE), it was originally felt that the vast majority of anaphylactic episodes were due to antigen coupling with two cell-bound IgE molecules. More recently it has been learned that many episodes are produced by direct activation of mast cells, not involving antigen binding to IgE, and that monomeric IgE under certain conditions can also cause degranulation. Of note—in regard to antigen independent degranulation—are recent reports that the human G-protein-coupled receptor, MRGPRX2, may be the receptor for many drugs and cationic proteins capable of producing direct mast cell degranulation and anaphylactic events.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Allergy in theory and practice. In: RA Cooke, ed. W. B. Saunders Company, Philadelphia, 1947.

  2. Avenberg KM, Harper DS, Larsson BL. Footnotes on allergy. Uppsala: Published by Pharmacia AB; 1980. p. 84–5.

    Google Scholar 

  3. Samter M. Excerpts from classics in allergy (edited for the 25th Anniversary Committee of the American Academy of Allergy, Asthma, and Immunology). Published by Ross Laboratories, Columbus; copyright 1969. Library of Congress Catalog Number 70-77908, 32–33.

  4. Riley JF, West GB. Histamine in tissue mast cells. J Physiol. 1952;117(4):72P–3.

    CAS  PubMed  Google Scholar 

  5. Mota I. Action of anaphylactic shock and anaphylatoxin on mast cells and histamine in rats. Brit J Pharmacol. 1957;12:453–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zayas E, da Silva M, Jamur MC, Oliver C. Mast cell function: a new vision of an old cell. J Histochem Cytochem. 2014;62(10):698–738. doi:10.1369/0022155414545334.

    Article  Google Scholar 

  7. Maaninka K, Lappalainen J, Kovanen PT. Human mast cells arise from a common circulating progenitor. J Allergy Clin Immunol. 2013;132(2):463–9. These investigators demonstrated conclusively that mast cells that reside in the mucosal tissue (known as MC mast cells) and mast cells that reside in the connective tissue (known as MCTC mast cells) have a common progenitor. They demonstrate that these cells assume their phenotypic profiles only upon reaching the tissue in which they reside after exiting the bone marrow.

  8. Theoharides TC, Valent P, Akin C. Mast cells, mastocytosis, and related disorders. N Engl J Med. 2015;373:163–72. doi:10.1056/NEJMra1409760. A superb and comprehensive review on the role of mast cells in the production of anaphylactic events with an emphasis on mast cell activation disorders such as systemic mastocytosis, urticaria pigmentosa, and other mast cell activating syndromes.

    Article  CAS  PubMed  Google Scholar 

  9. Bradding P, Feather IH, Wilson S, Bardin PG, Heusser CH, Holgate ST, et al. Immunolocalization of cytokines in the nasal mucosa of normal and perennial rhinitic subjects. The mast cell as a source of IL-4, IL-5, and IL-6 in human allergic mucosal inflammation. J Immunol. 1993;151(7):3853–65.

    CAS  PubMed  Google Scholar 

  10. Qu Z, Liebler JM, Powers MR, Galey T, Ahmadi P, Huang XN, et al. Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am J Pathol. 1995;147(3):564.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature. 1990;346(6281):274.

    Article  CAS  PubMed  Google Scholar 

  12. Jaffe JS, Glaum MC, Raible DG, Post TJ, Dimitry E, Govindarao D, et al. Human lung mast cell IL-5 gene and protein expression: temporal analysis of upregulation following IgE-mediated activation. Am J Respir Cell Mol Biol. 1995;13(6):665.

    Article  CAS  PubMed  Google Scholar 

  13. Bradding P, Saito H. Biology of mast cells and their mediators. In: Middleton’s Allergy: Principles and Practice, Ed 8, 228-251, 2014 (edited by N. Franklin Adkinson Jr., M.D., Bruce S. Bochner, M.D.).

  14. Weidner N, Horan RF, Austen KF. Mast-cell phenotype in indolent forms of mastocytosis. Ultrastructural features, fluorescence detection of avidin binding, and immunofluorescent determination of chymase, tryptase, and carboxypeptidase. Am J Pathol. 1992;140(4):847–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Bradding P, Okayama Y, Howarth PH, Church MK, Holgate ST. Heterogeneity of human mast cells based on cytokine content. J Immunol. 1995;155:297–307.

    CAS  PubMed  Google Scholar 

  16. Saito H, Ishizaka T, Ishizaka K. Mast cells and IgE: from history to today. Allergol Int. 2013;62(1):3–12. doi:10.2332/allergolint.13-RAI-0537. A comprehensive history of the relationship between IgE and the mast cell with a detailed description of the necessity for a divalent antigen bridging to adjacent cell-bound IgE molecules to produce mast cell degranulation.

    Article  CAS  PubMed  Google Scholar 

  17. Kishimoto TK, Viswanathan K, Ganguly T, Elankumaran S, Smith S, Pelzer K, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system. N Engl J Med. 2008;358:2457–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schwartz LB. Heparin comes clean. N Engl J Med. 2008;358:2505–9.

    Article  CAS  PubMed  Google Scholar 

  19. Kaplan AP, Hunt KJ, Sobotka AK, et al. Human anaphylaxis: a study of mediator systems. Clin Rev. 1977;25:361.

    Google Scholar 

  20. Van der Linden PW, Hack CE, Kerckhaert J, et al. Preliminary report: complement activation in wasp-sting anaphylaxis. Lancet. 1990;336:904–6.

    Article  PubMed  Google Scholar 

  21. Van Hagge-Hamsten M, Hack CE, Eerenberg AJ, et al. Contact system activation and angioedema in insect-sting anaphylaxis. J Allergy Clin Immunol. 1993;91:283.

    Google Scholar 

  22. Sala-Cunill A, Björkqvist J, Senter R, Guilarte M, Cardona V, Labrador M, et al. Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions. J Allergy Clin Immunol. 2015;135(4):1031–43. Demonstration that clinical events resembling IgE-induced classical anaphylactic reactions can occur through the activation of other pathways, in this case the contact system.

    Article  CAS  PubMed  Google Scholar 

  23. Phan C, Vial-Dupuy A, Autegarden JE, Amsler E, Gaouar H, Abuaf N, et al. A study of 19 cases of allergy to heparins with positive skin testing. Ann Dermatol Venereol. 2014;141(1):23–9. Agents which can activate the contact system are potentially capable of producing anaphylactic events through an IgE-mediated mechanism as well.

    Article  CAS  PubMed  Google Scholar 

  24. McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, et al. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature. 2015;519(7542):237–41. doi:10.1038/nature14022. The authors describe, for the first time, a cell surface receptor, Mrgprb2, in mice which is the orthologue of the human G-protein-coupled receptor MRGPRX2. They demonstrate that this receptor, in mice, is the receptor for multiple molecules including cationic proteins and many drugs that are known to produce anaphylactic events in the human. They cite examples of the secretagogues including neuromuscular blocking drugs, fluoroquinolones such as ciprofloxacin, and 40/80 inducing mast cell activation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Grimbaldeston MA. Mast cell-MrgprB2: sensing secretagogues or a means to overreact? Immunol Cell Biol. 2015;10.1038/icb.2015.10:221–3. In this manuscript, Dr. Grimbaldeston comments on the potential clinical importance of the previous reference (McNeil, et al.) noted above and comments on the potential clinical importance of their discovery. They also describe the downstream signaling pathway initiated by the binding of drugs such as fluoroquinolones, peptidergic drugs as Icatibant, and neuromuscular blocking drugs to MrgprB2 involving the phospholipase C-gamma pathway.

    Article  Google Scholar 

  26. Ishizaka T, Ishizaka K. Triggering of histamine release from rat mast cells by divalent antibodies against IgE-receptors. J Immunol. 1978;120(3):800–5.

    CAS  PubMed  Google Scholar 

  27. Cruse G, Kaur D, Yang W, et al. Activation of human lung mast cells by monomeric immunoglobulin E. Eur Resp J. 2005;25:858–63.

    Article  CAS  Google Scholar 

  28. Ying S, Humbert M, Meng Q, Pfister R, Menz G, Gould HJ, et al. Local expression of epsilon germline gene transcripts and RNA for the epsilon heavy chain of IgE in the bronchial mucosa in atopic and nonatopic asthma. J Allergy Clin Immunol. 2001;107(4):686–92.

    Article  CAS  PubMed  Google Scholar 

  29. Meltzer EO, Berkowitz RB, Grossbard EB. An intranasal Syk-kinase inhibitor (R112) improves the symptoms of seasonal allergic rhinitis in a park environment. J Allergy Clin Immunol. 2005;115(4):791–6.

    Article  CAS  PubMed  Google Scholar 

  30. Arock M, Akin C, Hermine O, Valent P. Current treatment options in patients with mastocytosis: status in 2015 and future perspectives. Eur J Haematol. 2015;94(6):474–90. A discussion of the treatment modalities available for the management of mastocytosis and mast cell activating disorders.

    Article  PubMed  Google Scholar 

  31. Yang Y, Lu JY, Wu X, Summer S, Whoriskey J, Saris C, et al. G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium. Pharmacology. 2010;86(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  32. Karra L, Levi-Schaffer F. Down-regulation of mast cell responses through ITIM containing inhibitory receptors. Adv Exp Med Biol. 2011;716:143–59.

    Article  CAS  PubMed  Google Scholar 

  33. Patterson R, Fitzsimons EJ, Choy AC, Harris KE. Malignant and corticosteroid-dependent idiopathic anaphylaxis: successful responses to ketotifen. Ann Allergy Asthma Immunol. 1997;79(2):138–44.

    Article  CAS  PubMed  Google Scholar 

  34. Akin C. Mast cell activation syndromes presenting as anaphylaxis. Immunol Allergy Clin North Am. 2015;35(2):277–85. doi:10.1016/j.iac.2015.01.010. A thorough review and classification of mast cell disorders and their relation to anaphylaxis.

    Article  PubMed  Google Scholar 

  35. Akin C, Scott LM, Kocabas CN, Kushnir-Sukhov N, Brittain E, Noel P, et al. Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis. Blood. 2007;110:2331–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classifications of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Archives Allergy Immunol. 2012;157:215–25.

    Article  Google Scholar 

  37. Horny HP, Metcalfe DD, Bennett JM, Bain BJ, Akin C, Escribano L, et al. Mastocytosis. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2008. p. 54–63.

    Google Scholar 

  38. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Systemic reactions after hymenoptera sting and raised serum tryptase strongly suggest clonal mast cells disorders. J Allergy Clin Immunol. 2009;123(2 Supplement):S242.

    Article  Google Scholar 

  39. Schumacher JA, Alentoba-Johnson KS, Lim MS. Detection of the c-KIT D816V in SM patients. J Clin Pathol. 2008;61(1):109–14.

    Article  CAS  PubMed  Google Scholar 

  40. Paul C, Sans B, Suarez F, Casassus P, Barete S, Lanternier F, et al. Masitinib for the treatment of systemic and cutaneous mastocytosis with handicap: a phase 2a study. Am J Hematol. 2010;85(12):921–5.

    Article  CAS  PubMed  Google Scholar 

  41. Shanmugam G, Schwartz LB, Khan DA. Prolonged elevation of serum tryptase in idiopathic anaphylaxis. J Allergy Clin Immunol. 2006;117(4):950–1.

    Article  CAS  PubMed  Google Scholar 

  42. Vinuya RZ, Simon MR, Schwartz LB. Elevated serum tryptase levels in a patient with protracted anaphylaxis. Ann Allergy. 1994;73(3):232–4.

    CAS  PubMed  Google Scholar 

  43. Lin RY, Schwartz LB, Curry A, Pesola GR, Knight RJ, Lee HS, et al. Histamine and tryptase levels in patients with acute allergic reactions: an emergency department-based study. J Allergy Clin Immunol. 2000;106:65–71.

    Article  CAS  PubMed  Google Scholar 

  44. Butterfield JH, Weiler CR. Prevention of mast cell activation disorder-associated clinical sequelae of excessive prostaglandin D(2) production. Int Arch Allergy Immunol. 2008;147:338.

    Article  CAS  PubMed  Google Scholar 

  45. Rank MA, Kita H, Li JT, Butterfield JH. Systemic reactions to allergen immunotherapy: a role for measuring a PGD2 metabolite? Ann Allergy Asthma Immunol. 2013;110(1):57–8. doi:10.1016/j.anai.2012.10.009.

    Article  CAS  PubMed  Google Scholar 

  46. Bonadonna P, Perbellini O, Passalacqua G, Caruso B, Colarossi S, Dal Fior D, et al. Clonal mast cell disorders in patients with systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin Immunol. 2009;123:680–6.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Divisions of Allergy and Immunology, Departments of Medicine and Pediatrics, University of Tennessee, Memphis, TN, USA

    Phil Lieberman

  2. 7205 Wolf River Blvd., Suite 200, Germantown, TN, 38138-1777, USA

    Phil Lieberman

  3. Allergy Clinic UA-816, Department of Dermato-allergology, Copenhagen University Hospital, Gentofte, Kildegårdsvej 28, DK-2900, Hellerup, Denmark

    Lene Heise Garvey

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Dr. Lieberman reports that he is a speaker for Mylan and Teva. Dr. Garvey declares no conflict of interest.

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This article is part of the Topical Collection on Anaphylaxis and Drug Allergy

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Lieberman, P., Garvey, L.H. Mast Cells and Anaphylaxis. Curr Allergy Asthma Rep 16, 20 (2016). https://doi.org/10.1007/s11882-016-0598-5

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