Reviews and feature article
Mechanisms of mast cell signaling in anaphylaxis

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The recent development of a consensus definition and proposed diagnostic criteria for anaphylaxis offers promise for research efforts and a better understanding of the epidemiology and pathogenesis of this enigmatic and life-threatening disease. This review examines basic principles and recent research advances in the mechanisms of mast cell signaling believed to underlie anaphylaxis. The unfolding complexity of mast cell signaling suggests that the system is sensitive to regulation by any of several individual signaling pathways and intermediates and that complementary pathways regulate mast cell activation by amplified signals. The signaling events underlying anaphylactic reactions have largely been identified through experiments in genetically modified mice and supported by biochemical studies of mast cells derived from these mice. These studies have revealed that signaling pathways exist to both upregulate and downregulate mast cell responses. In this review we will thus describe the key molecular players in these pathways in the context of anaphylaxis.

Section snippets

Mast cell mediators and mechanisms of release

Anaphylaxis occurs rapidly and systemically, affecting 1 or more organ systems, generally where mast cells reside in relative abundance.2, 7 Underlying the pathophysiology of anaphylaxis is exposure to allergen or other factors that activate mast cells or basophils, prompting degranulation and immediate (5-30 minutes) release of preformed mediators (histamine, tryptase, carboxypeptidase A, and proteoglycans), synthesis of arachidonic acid metabolites (prostaglandins, leukotrienes), and

Mast cell signaling

The signaling cascades that regulate mast cell activation have been extensively investigated during the past few years and are described in depth in recent reviews.21, 22, 23 In this review the basic principles involved in the regulation of mast cell activation are described relative to the anaphylactic response and focus on the contributions of degranulation and immediately released mediators. The relevance of these studies to our understanding of the role of basophils in anaphylaxis is not

Conclusion

Advances in mast cell signaling research have improved our understanding of the pathophysiology of anaphylaxis. The identification of signaling pathways and components that amplify signals or alter the threshold of activation of mast cells, leading to degranulation and mediator release, has the promise of identifying novel approaches for prevention and treatment of anaphylaxis. The discovery of polymorphisms and mutations in components that regulate mast cell signaling might lead to ways to

References (71)

  • C. Akin et al.

    Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with “idiopathic” anaphylaxis

    Blood

    (2007)
  • C. Akin et al.

    Occult bone marrow mastocytosis presenting as recurrent systemic anaphylaxis in patients with systemic mastocytosis

    J Allergy Clin Immunol

    (2003)
  • M.C. Carter et al.

    Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis

    J Allergy Clin Immunol

    (2007)
  • J. Rivera et al.

    Molecular regulation of mast cell activation

    J Allergy Clin Immunol

    (2006)
  • H.S. Kuehn et al.

    G protein-coupled receptors and the modification of FcεRI-mediated mast cell activation

    Immunol Lett

    (2007)
  • R.M. Young et al.

    A lipid raft environment enhances Lyn kinase activity by protecting the active site tyrosine from dephosphorylation

    J Biol Chem

    (2003)
  • M.L. Hibbs et al.

    Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease

    Cell

    (1995)
  • S. Saitoh et al.

    LAT is essential for FcεRI-mediated mast cell activation

    Immunity

    (2000)
  • S. Iwaki et al.

    Kit- and FcεRI-induced differential phosphorylation of the transmembrane adaptor molecule NTAL/LAB/LAT2 allows flexibility in its scaffolding function in mast cells

    Cell Signal

    (2008)
  • C. Tkaczyk et al.

    The phospholipase Cγ1-dependent pathway of FcεRI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase

    J Biol Chem

    (2003)
  • J. Liou et al.

    STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx

    Curr Biol

    (2005)
  • M.S. Kim et al.

    The multiple roles of phosphoinositide 3-kinase in mast cell biology

    Trends Immunol

    (2008)
  • M. Laffargue et al.

    Phosphoinositide 3-kinase γ is an essential amplifier of mast cell function

    Immunity

    (2002)
  • A. Olivera et al.

    The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis

    Immunity

    (2007)
  • A. Olivera et al.

    IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses

    J Biol Chem

    (2006)
  • A.J. Melendez et al.

    Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells

    J Biol Chem

    (2002)
  • P. Lieberman

    Epidemiology of anaphylaxis

    Curr Opin Allergy Clin Immunol

    (2008)
  • K. Lenchner et al.

    A current review of idiopathic anaphylaxis

    Curr Opin Allergy Clin Immunol

    (2003)
  • J. Ring et al.

    Idiopathic anaphylaxis

    Curr Allergy Asthma Rep

    (2002)
  • N. Nieuwenhuizen et al.

    CD4 + T cell-specific deletion of IL-4 receptor alpha prevents ovalbumin-induced anaphylaxis by an IFN-γ-dependent mechanism

    J Immunol

    (2007)
  • H. Nagata 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 associate hematologic disorder

    Proc Natl Acad Sci USA

    (1995)
  • D. González de Olano et al.

    Prevalence of allergy and anaphylactic symptoms in 210 adult and pediatric patients with mastocytosis in Spain: a study of the Spanish network on mastocytosis (REMA)

    Clin Exp Allergy

    (2007)
  • J.M. Brown et al.

    The mast cell and allergic disease: role in pathogenesis and implications for therapy

    Clin Exp Allergy

    (2008)
  • A.M. Gilfillan et al.

    Integrated signalling pathways for mast-cell activation

    Nat Rev Immunol

    (2006)
  • S. Kraft et al.

    New developments in FcεRI regulation, function and inhibition

    Nat Rev Immunol

    (2007)
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    (Supported by an educational grant from Merck & Co., Inc.)

    Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD

    Supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

    Terms in boldface and italics are defined in the glossary on page 640.

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