Top

Published in:

01-02-2013 | BASIC AND APPLIED SCIENCE (M FRIERI, SECTION EDITOR)

Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome

Authors: Juan-Carlos Cardet, Mariana C. Castells, Matthew J. Hamilton

Published in: Current Allergy and Asthma Reports | Issue 1/2013

Abstract

There is a spectrum of disorders that clinically manifest as a result of mast cell activation. A non-clonal form has emerged in the literature where many of the clinical features of systemic mastocytosis are shared despite having a distinct mast cell biology. In this review, we summarize key features of the science behind mast cell activation relevant to what is now known as non-clonal mast cell activation syndrome (nc-MCAS). We highlight the clinical manifestations of nc-MCAS with a focus on diagnosis and treatment.

Valent P, Akin C, Escribano L, Fodinger M, Hartmann K, Brockow K, et al. Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria. Eur J Clin Investig. 2007;37(6):435–53. PubMed PMID: 17537151. Epub 2007/06/01. eng.CrossRef

Roberts 2nd LJ, Oates JA. Biochemical diagnosis of systemic mast cell disorders. J Investig Dermatol. 1991;96(3):19S–24. discussion S-5S. PubMed PMID: 2002247. Epub 1991/03/01. eng.CrossRef

Frieri M. Anaphylaxis. In: Raoof S, editor. Manual of critical care. Philadelphia, PA: American College of Physicians, McGraw Hill Co; 2009. p. 721–30.

• Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol. 2010;126(6):1099–104 e4. PubMed PMID: 21035176. Epub 2010/11/03. eng. This article summarizes the consensus conference where experts proposed diagnostic criteria for non-clonal (idiopathic) mast cell activation syndrome as a distinct disease entity.PubMedCrossRef

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. PubMed PMID: 21418662. Pubmed Central PMCID: 3069946. Epub 2011/03/23. eng.PubMedCrossRef

Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol. 2012;157(3):215–25. PubMed PMID: 22041891. Pubmed Central PMCID: 3224511. Epub 2011/11/02. eng.PubMedCrossRef

Metcalfe DD. Mast cells and mastocytosis. Blood. 2008;112(4):946–56. PubMed PMID: 18684881. Pubmed Central PMCID: 2515131. Epub 2008/08/08. eng.PubMedCrossRef

Galli SJ, Grimbaldeston M, Tsai M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat Rev Immunol. 2008;8(6):478–86. PubMed PMID: 18483499. Pubmed Central PMCID: 2855166. Epub 2008/05/17. eng.PubMedCrossRef

Frieri M. Mastocytosis. In: Mahmoudi M, editor. Challenges Cases in Allergy Immunology: Humana Press; 2009. p. 201–12.

10.

Brown JM, Wilson TM, Metcalfe DD. The mast cell and allergic diseases: role in pathogenesis and implications for therapy. Clin Exp allergy J Br Soc Allergy Clin Immunol. 2008;38(1):4–18. PubMed PMID: 18031566. Epub 2007/11/23. eng.

11.

Nagata H, Worobec AS, Oh CK, Chowdhury BA, Tannenbaum S, Suzuki Y, et al. Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. Proc Natl Acad Sci U S A. 1995;92(23):10560–4. PubMed PMID: 7479840. Pubmed Central PMCID: 40651. Epub 1995/11/07. eng.PubMedCrossRef

12.

Bodemer C, Hermine O, Palmerini F, Yang Y, Grandpeix-Guyodo C, Leventhal PS, et al. Pediatric mastocytosis is a clonal disease associated with D816V and other activating c-KIT mutations. J Investig Dermatol. 2010;130(3):804–15. PubMed PMID: 19865100. Epub 2009/10/30. eng.PubMedCrossRef

13.

Molderings GJ, Kolck UW, Scheurlen C, Bruss M, Homann J, Von Kugelgen I. Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scand J Gastroenterol. 2007;42(9):1045–53. PubMed PMID: 17710669. Epub 2007/08/22. eng.PubMedCrossRef

14.

Molderings GJ, Meis K, Kolck UW, Homann J, Frieling T. Comparative analysis of mutation of tyrosine kinase kit in mast cells from patients with systemic mast cell activation syndrome and healthy subjects. Immunogenetics. 2010;62(11–12):721–7. PubMed PMID: 20838788. Epub 2010/09/15. eng.PubMedCrossRef

15.

Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy Clin. 2006;26(3):465–85. PubMed PMID: 16931289. Epub 2006/08/26. eng.

16.

Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D. Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev. 2007;217:65–78. PubMed PMID: 17498052. Epub 2007/05/15. eng.PubMedCrossRef

17.

Kulka M, Alexopoulou L, Flavell RA, Metcalfe DD. Activation of mast cells by double-stranded RNA: evidence for activation through Toll-like receptor 3. J Allergy Clin Immunol. 2004;114(1):174–82. PubMed PMID: 15241362. Epub 2004/07/09. eng.PubMedCrossRef

18.

Woolhiser MR, Brockow K, Metcalfe DD. Activation of human mast cells by aggregated IgG through FcgammaRI: additive effects of C3a. Clin Immunol. 2004;110(2):172–80. PubMed PMID: 15003814. Epub 2004/03/09. eng.PubMedCrossRef

19.

Rivera J, Gilfillan AM. Molecular regulation of mast cell activation. J Allergy Clin Immunol. 2006;117(6):1214–25. quiz 26. PubMed PMID: 16750977. Epub 2006/06/06. eng.PubMedCrossRef

20.

Katz HR. Inhibitory receptors and allergy. Curr Opin Immunol. 2002;14(6):698–704. PubMed PMID: 12413518. Epub 2002/11/05. eng.PubMedCrossRef

21.

Castells MC, Klickstein LB, Hassani K, Cumplido JA, Lacouture ME, Austen KF, et al. gp49B1-alpha(v)beta3 interaction inhibits antigen-induced mast cell activation. Nat Immunol. 2001;2(5):436–42. PubMed PMID: 11323698. Epub 2001/04/27. eng.PubMed

22.

Kandere-Grzybowska K, Letourneau R, Kempuraj D, Donelan J, Poplawski S, Boucher W, et al. IL-1 induces vesicular secretion of IL-6 without degranulation from human mast cells. J Immunol. 2003;171(9):4830–6. PubMed PMID: 14568962. Epub 2003/10/22. eng.PubMed

23.

Varadaradjalou S, Feger F, Thieblemont N, Hamouda NB, Pleau JM, Dy M, et al. Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. Eur J Immunol. 2003;33(4):899–906. PubMed PMID: 12672055. Epub 2003/04/03. eng.PubMedCrossRef

24.

Dvorak AM, Tepper RI, Weller PF, Morgan ES, Estrella P, Monahan-Earley RA, et al. Piecemeal degranulation of mast cells in the inflammatory eyelid lesions of interleukin-4 transgenic mice. Evidence of mast cell histamine release in vivo by diamine oxidase-gold enzyme-affinity ultrastructural cytochemistry. Blood. 1994;83(12):3600–12. PubMed PMID: 7515717. Epub 1994/06/15. eng.PubMed

25.

Dvorak AM, McLeod RS, Onderdonk A, Monahan-Earley RA, Cullen JB, Antonioli DA, et al. Ultrastructural evidence for piecemeal and anaphylactic degranulation of human gut mucosal mast cells in vivo. Int Arch Allergy Immunol. 1992;99(1):74–83. PubMed PMID: 1483068. Epub 1992/01/01. eng.PubMedCrossRef

26.

Dvorak AM. Piecemeal degranulation of basophils and mast cells is effected by vesicular transport of stored secretory granule contents. Chem Immunol Allergy. 2005;85:135–84. PubMed PMID: 15970657. Epub 2005/06/23. eng.PubMedCrossRef

27.

Gilfillan AM, Tkaczyk C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol. 2006;6(3):218–30. PubMed PMID: 16470226. Epub 2006/02/14. eng.PubMedCrossRef

28.

Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007;85(5):1185–96. PubMed PMID: 17490952. Epub 2007/05/11. eng.PubMed

29.

Castells M, Austen KF. Mastocytosis: mediator-related signs and symptoms. Int Arch Allergy Immunol. 2002;127(2):147–52. PubMed PMID: 11919427. Epub 2002/03/29. eng.PubMedCrossRef

30.

• Hamilton MJ, Hornick JL, Akin C, Castells MC, Greenberger NJ. Mast cell activation syndrome: a newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 2011;128(1):147–52 e2. PubMed PMID: 21621255. Epub 2011/05/31. eng. This study reports on valuable clinical data of patients with non-clonal mast cell activation syndrome. Provides data on therapeutic response to the stepwise approach of mast cell mediator blockade.PubMedCrossRef

31.

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(4):338–43. PubMed PMID: 18622141. Epub 2008/07/16. eng.PubMedCrossRef

32.

Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316(26):1622–6. PubMed PMID: 3295549. Epub 1987/06/25. eng.PubMedCrossRef

33.

Frieri M PR, Celestin J Mast Cell Activation Syndrome: A Review. Current allergy and asthma reports. 2012;published in this issue.

34.

Akin C. Anaphylaxis and mast cell disease: what is the risk? Curr Allergy Asthma Rep. 2010;10(1):34–8. PubMed PMID: 20425512. Epub 2010/04/29. eng.PubMedCrossRef

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(7):2331–3. PubMed PMID: 17638853. Pubmed Central PMCID: 1988935. Epub 2007/07/20. eng.PubMedCrossRef

36.

Metcalfe DD. Differential diagnosis of the patient with unexplained flushing/anaphylaxis. Allergy Asthma Proc official J Reg State Allergy Soc. 2000;21(1):21–4. PubMed PMID: 10748948. Epub 2000/04/05. eng.CrossRef

37.

•• Alvarez-Twose I, Gonzalez De Olano D, Sanchez-Munoz L, Matito A, Esteban-Lopez MI, Vega A, et al. Clinical, biological, and molecular characteristics of clonal mast cell disorders presenting with systemic mast cell activation symptoms. J Allergy Clin Immunol. 2010;125(6):1269–78 e2. PubMed PMID: 20434205. Epub 2010/05/04. eng. This study compares clinical and laboratory characteristics of different groups with mast cell disease, including non-clonal and monoclonal mast cell activation syndrome, in addition to those with systemic mastocytosis. Offers a predictive formula for monoclonality for patients with a clinical picture suggestive of mast cell activation, based on clinical assessments.PubMedCrossRef

38.

Kassab D, Koterba A, Jiang Y, Akin C. Elevated baseline tryptase levels in patients with mast cell activation syndromes without evidence of mastocytosis. J Allergy Clin Immunol. 2008;121(2):S67.CrossRef

39.

Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25(7):603–25. PubMed PMID: 11377686. Epub 2001/05/30. eng.PubMedCrossRef

40.

Frieri M, Linn N, Schweitzer M, Angadi C, Pardanani B. Lymphadenopathic mastocytosis with eosinophilia and biclonal gammopathy. J Allergy Clin Immunol. 1990;86(1):126–32.PubMedCrossRef

41.

Lindner PS, Pardanani B, Angadi C, Frieri M. Acute nonlymphocytic leukemia in systemic mastocytosis with biclonal gammopathy. J Allergy Clin Immunol. 1992;90(3 Pt 1):410–2.PubMedCrossRef

42.

Sonneck K, Florian S, Mullauer L, Wimazal F, Fodinger M, Sperr WR, et al. Diagnostic and subdiagnostic accumulation of mast cells in the bone marrow of patients with anaphylaxis: monoclonal mast cell activation syndrome. Int Arch Allergy Immunol. 2007;142(2):158–64. PubMed PMID: 17057414. Epub 2006/10/24. eng.PubMedCrossRef

43.

Escribano L, Diaz-Agustin B, Lopez A, Nunez Lopez R, Garcia-Montero A, Almeida J, et al. Immunophenotypic analysis of mast cells in mastocytosis: when and how to do it. Proposals of the Spanish Network on Mastocytosis (REMA). Cytometry B Clin Cytom. 2004;58(1):1–8. PubMed PMID: 14994369. Epub 2004/03/03. eng.PubMedCrossRef

44.

Escribano L, Diaz-Agustin B, Bellas C, Navalon R, Nunez R, Sperr WR, et al. Utility of flow cytometric analysis of mast cells in the diagnosis and classification of adult mastocytosis. Leuk Res. 2001;25(7):563–70. PubMed PMID: 11377681. Epub 2001/05/30. eng.PubMedCrossRef

45.

Akin C. Molecular diagnosis of mast cell disorders: a paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology. J Mol Diagnostics. 2006;8(4):412–9. PubMed PMID: 16931579. Pubmed Central PMCID: 1867614. Epub 2006/08/26. eng.CrossRef

46.

Garcia-Montero AC, Jara-Acevedo M, Teodosio C, Sanchez ML, Nunez R, Prados A, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders: a prospective study of the Spanish Network on Mastocytosis (REMA) in a series of 113 patients. Blood. 2006;108(7):2366–72. PubMed PMID: 16741248. Epub 2006/06/03. eng.PubMedCrossRef

47.

Worobec AS, Semere T, Nagata H, Metcalfe DD. Clinical correlates of the presence of the Asp816Val c-kit mutation in the peripheral blood mononuclear cells of patients with mastocytosis. Cancer. 1998;83(10):2120–9. PubMed PMID: 9827716. Epub 1998/11/25. eng.PubMedCrossRef

48.

Horny HP, Sotlar K, Valent P. Evaluation of mast cell activation syndromes: impact of pathology and immunohistology. Int Arch Allergy Immunol. 2012;159(1):1–5. PubMed PMID: 22555026. Epub 2012/05/05. eng.PubMedCrossRef

49.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in gastrointestinal mucosal mast cells is specific for systemic mastocytosis. Am J Surg Pathol. 2007;31(11):1669–76. PubMed PMID: 18059223. Epub 2007/12/07. eng.PubMedCrossRef

50.

Schwartz LB. Clinical utility of tryptase levels in systemic mastocytosis and associated hematologic disorders. Leuk Res. 2001;25(7):553–62. PubMed PMID: 11377680. Epub 2001/05/30. eng.PubMedCrossRef

51.

Hogan AD, Schwartz LB. Markers of mast cell degranulation. Methods. 1997;13(1):43–52. PubMed PMID: 9281467. Epub 1997/09/01. eng.PubMedCrossRef

52.

Sargur R, Cowley D, Murng S, Wild G, Green K, Shrimpton A, et al. Raised tryptase without anaphylaxis or mastocytosis: heterophilic antibody interference in the serum tryptase assay. Clin Exp Immunol. 2011;163(3):339–45. PubMed PMID: 21303361. Pubmed Central PMCID: 3048617. Epub 2011/02/10. eng.PubMedCrossRef

53.

Oosting E, Neugebauer E, Keyzer JJ, Lorenz W. Determination of histamine in human plasma: the European external quality control study 1988. Clin Exp allergy J Br Soc Allergy Clin Immunol. 1990;20(4):349–57. PubMed PMID: 2198083. Epub 1990/07/01. eng.CrossRef

54.

Awad JA, Morrow JD, Roberts 2nd LJ. Detection of the major urinary metabolite of prostaglandin D2 in the circulation: demonstration of elevated levels in patients with disorders of systemic mast cell activation. J Allergy Clin Immunol. 1994;93(5):817–24. PubMed PMID: 8182221. Epub 1994/05/01. eng.PubMedCrossRef

55.

Frieri M, Alling DW, Metcalfe DD. Comparison of the therapeutic efficacy of cromolyn sodium with that of combined chlorpheniramine and cimetidine in systemic mastocytosis. Results of a double-blind clinical trial. Am J Med. 1985;78(1):9–14.PubMedCrossRef

56.

Douglass JA, Carroll K, Voskamp A, Bourke P, Wei A, O'Hehir RE. Omalizumab is effective in treating systemic mastocytosis in a nonatopic patient. Allergy. 2010;65(7):926–7. PubMed PMID: 19889117. Epub 2009/11/06. eng.PubMedCrossRef

57.

Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol. 2007;119(6):1550–1.PubMedCrossRef

58.

Bell MC, Jackson DJ. Prevention of anaphylaxis related to mast cell activation syndrome with omalizumab. Ann Allergy Asthma Immunol official publ Am Coll Allergy Asthma Immunol. 2012;108(5):383–4. PubMed PMID: 22541416. Pubmed Central PMCID: 3340573. Epub 2012/05/01. eng.CrossRef

59.

Molderings GJ, Raithel M, Kratz F, Azemar M, Haenisch B, Harzer S, et al. Omalizumab treatment of systemic mast cell activation disease: experiences from four cases. Intern Med. 2011;50(6):611–5. PubMed PMID: 21422688. Epub 2011/03/23. eng.PubMedCrossRef

60.

Afrin LB. Polycythemia from mast cell activation syndrome: lessons learned. Am J Med Sci. 2011;342(1):44–9. PubMed PMID: 21642812. Epub 2011/06/07. eng.PubMedCrossRef

61.

Afrin LB. Mast cell activation syndrome masquerading as agranulocytosis. Military Med. 2012;177(1):113–7. PubMed PMID: 22338992. Epub 2012/02/22. eng.

62.

Afrin LB. Burning mouth syndrome and mast cell activation disorder. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;111(4):465–72. PubMed PMID: 21420635. Epub 2011/03/23. eng.PubMedCrossRef

63.

Afrin LB. Sclerosing mediastinitis and mast cell activation syndrome. Pathol Res Pract. 2012;208(3):181–5. PubMed PMID: 22296862. Epub 2012/02/03. eng.PubMedCrossRef

64.

Gonzalez-de-Olano D, Matito A, Sanchez-Lopez P, Sanchez-Munoz L, Morgado JM, Teodosio C, et al. Mast cell-related disorders presenting with Kounis syndrome. Int J Cardiol. 2012;161(1):56–8. PubMed PMID: 22748285. Epub 2012/07/04. eng.PubMedCrossRef

65.

Bilo MB, Frontini F, Massaccesi C, Cinti B, Antonicelli L. Mast cell diseases and the severity and course of intraoperative anaphylaxis. Ann Allergy Asthma Immunol official publ Am Coll Allergy Asthma Immunol. 2009;103(2):175–6. PubMed PMID: 19739433. Epub 2009/09/11. eng.CrossRef

66.

Brockow K, Jofer C, Behrendt H, Ring J. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy. 2008;63(2):226–32. PubMed PMID: 18186813. Epub 2008/01/12. eng.PubMedCrossRef

67.

Brockow K, Bonadonna P. Drug allergy in mast cell disease. Curr Opin Allergy Clin Immunol. 2012;12(4):354–60. PubMed PMID: 22744266. Epub 2012/06/30. eng.PubMedCrossRef

68.

Slee V, RN, BSN. Emergency Room Protocol: The Mastocytosis Society, Inc.; 2010 [cited 2010 2010].

69.

Shibao C, Arzubiaga C, Roberts 2nd LJ, Raj S, Black B, Harris P, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005;45(3):385–90. PubMed PMID: 15710782. Epub 2005/02/16. eng.PubMedCrossRef

70.

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. PubMed PMID: 1562049. Pubmed Central PMCID: 1886368.PubMed

71.

Sheffer AL, Tong AK, Murphy GF, Lewis RA, McFadden Jr ER, Austen KF. Exercise-induced anaphylaxis: a serious form of physical allergy associated with mast cell degranulation. J Allergy Clin Immunol. 1985;75(4):479–84.PubMedCrossRef

72.

Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol. 2011;12(4):259–70.PubMedCrossRef

Title: Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome
Authors: Juan-Carlos Cardet
Mariana C. Castells
Matthew J. Hamilton
Publication date: 01-02-2013
Publisher: Current Science Inc.
Published in: Current Allergy and Asthma Reports / Issue 1/2013
Print ISSN: 1529-7322
Electronic ISSN: 1534-6315
DOI: https://doi.org/10.1007/s11882-012-0326-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2013

Immune Response to Nanomaterials: Implications for Medicine and Literature Review

Personalised Medicine and Asthma Diagnostics/Management

Mast Cell Activation Syndrome: A Review

Role of Nuclear Factor-ĸB in Breast and Colorectal Cancer

Update on the Performance and Application of Basophil Activation Tests

Mucosal Immunology and Probiotics