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Regulation of mast-cell and basophil function and survival by IgE

Nature Reviews Immunology volume 2, pages 773–786 (2002)Cite this article

Key Points

  • Mast cells and basophils are important sources of effector function in IgE-associated immune responses and are also potential sources of immunoregulatory function.

  • The best-understood mechanism for eliciting IgE-dependent effector function in mast cells and basophils is aggregation of FcɛRI, for example, by the crosslinking of FcɛRI-bound IgE with multivalent antigen.

  • Protein-tyrosine kinase (PTK)-mediated activation mechanisms are triggered by FcɛRI aggregation. Several adaptor proteins and enzymes are involved in the activation of crucial signalling pathways, which lead to degranulation, lipid-mediator release, and cytokine and chemokine production and secretion.

  • Inhibitory receptors, such as FcγRIIB, gp49B1, paired immunoglobulin-like receptor B (PIRB) and mast-cell function-associated antigen (MAFA) inhibit cell activation by using their immunoreceptor tyrosine-based inhibitory motifs (ITIMs) to recruit the SH2-domain-containing protein tyrosine phosphatases SHP1 and SHP2, or SH2-domain-containing inositol polyphosphate 5′ phosphatase 1 (SHIP1) and SHIP2.

  • Binding of monomeric IgE to FcɛRI enhances the surface expression of FcɛRI, which is associated with increased sensitivity to antigen challenge and the increased production of mediators and cytokines after FcɛRI aggregation.

  • Binding of monomeric IgE to FcɛRI can also enhance mast-cell survival, although the mechanism(s) that underlies this effect is not fully understood.

  • Mast-cell development and growth are crucially regulated by the survival and developmental factor c-KIT ligand (stem-cell factor, SCF). However, many other cytokines can positively (for example, IL-3, IL-4 and IL-6) or negatively (for example, transforming growth factor-β) affect the survival and/or proliferation of various mast-cell populations.

  • IL-3 is an important basophil survival and developmental factor, and it promotes basophilia in mice in vivo. However, IL-3 is not required for baseline levels of basophil production in mice.

  • Depending on the circumstances, FcɛRI aggregation can enhance mast-cell survival and/or proliferation, promote apoptosis or have neutral effects on survival.

  • Life-versus-death decisions in mast cells are influenced by many endogenous and exogenous factors. Endogenous factors include mast-cell-derived cytokines, cytokine receptors, adhesion molecules, death receptors, caspases, BCL-2-family proteins, intracellular signalling molecules (lipids and proteins) and transcription factors.

  • The effects of IgE on FcɛRI surface expression and survival of mast cells and basophils are additional potential targets for anti-IgE therapy of allergic diseases.

Abstract

Mast cells and basophils are important effector cells in T helper 2 (TH2)-cell-dependent, immunoglobulin-E-associated allergic disorders and immune responses to parasites. The crosslinking of IgE that is bound to the high-affinity receptor FcɛRI with multivalent antigen results in the aggregation of FcɛRI and the secretion of products that can have effector, immunoregulatory or autocrine effects. This response can be enhanced markedly in cells that have been exposed to high levels of IgE, which results in the increased surface expression of FcɛRI. Moreover, recent work indicates that monomeric IgE (in the absence of crosslinking) can render mast cells resistant to apoptosis induced by growth-factor deprivation in vitro and, under certain circumstances, can induce the release of cytokines. So, the binding of IgE to FcɛRI might influence mast-cell and basophil survival directly or indirectly, and can also regulate cellular function.

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Figure 1: FcɛRI-mediated activation pathways.
Figure 2: A representative inhibitory pathway in mast cells.
Figure 3: A positive-feedback model for IgE production and IgE-dependent mast-cell activation, survival and/or proliferation.

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Acknowledgements

We thank the members of the Kawakami and Galli laboratories for their valuable contributions to some of the studies reviewed here. We also thank B. Goldstein, D. MacGlashan Jr, H. Metzger, J. Rivera, S.-Y. Tam and M. Tsai for their critical review of the manuscript, A. M. Dvorak for the electron micrograph in Box 1, and J.-P. Kinet for the figure in Box 2. We apologize to those authors whose studies are not cited because of space limitations. This work was supported, in part, by grants from the National Institutes of Health to T.K. and S.J.G. This is publication number 492 from the La Jolla Institute for Allergy and Immunology.

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Authors and Affiliations

  1. Division of Allergy, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, 92121, California, USA

    Toshiaki Kawakami

  2. Departments of Pathology, and Immunology and Microbiology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, 94305-5324, California, USA

    Stephen J. Galli

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  1. Toshiaki Kawakami
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Correspondence to Stephen J. Galli.

Related links

Related links

DATABASES

InterPro

ITAM

PH

SH2

LocusLink

A1

AFX

AKT

BAD

Bax

Bcl-2

BCL-XL

BTK

caspase-9

CD23

c-Fos

c-Jun

c-Kit

DOK1

ERK1

ERK2

FAS

FASL

FcɛRI

FcγRII

FcγRIIB

FcγRIII

fibronectin

FKHR

FKHRL1

GAB2

galectin-3

GM-CSF

GRB2

ICAM1

IκB

IL-2

IL-3

IL-4

IL-5

IL-6

IL-9

IL-10

IL-13

interferon-γ

JNK1

JNK2

JunB

laminin

LAT

LFA1

LYN

MAFA

MIP1α

NFAT

NF-κB

NGF

PDGF

PI3K

PIRB

PLCγ

PTEN

p70 S6 kinases

p90RSK

RAC2

SCF

SHC

SHIP

SHP1

SHP2

SLP76

SOS

SRC

Stat5

SYK

α-subunit

β-subunit

γ-subunit

TEC

TGF-β1

THY1

TNF

TRAIL

VAV

vitronectin

OMIM

asthma

FURTHER INFORMATION

The Fourth International Workshop on Signal Transduction in the Activation and Development of Mast cells and Basophils, 2001

Glossary

ATOPY

A word meaning 'strange disease' that was coined to describe the familial syndrome of asthma and hay fever. Atopic subjects are predisposed to develop strong IgE responses to common environmental antigens.

T HELPER 2 CELL

(TH2 cell). A type of T cell that, through the production of IL-4, IL-13 and other cytokines, can help B cells to produce IgE and other antibodies and, through the secretion of IL-5, IL-3 and others, can promote increased numbers of eosinophilic granulocytes (eosinophils), basophils and mast cells.

ITAM

(Immunoreceptor tyrosine-based activation motif). A sequence — YxxL/I(x)6–8YxxL/I — that is present in the cytoplasmic domains of various activating receptors on immune cells, including FcɛRI, that has a crucial role in recruiting SRC- and SYK-family protein-tyrosine kinases.

LIPID RAFTS

Areas of the plasma membrane that are rich in cholesterol, glycosphingolipids, several signalling proteins (such as SRC kinases, RAS, LAT, CBP/PAG) and glycosylphosphatidylinositol-anchored proteins. Also known as glycolipid-enriched microdomains (GEMs) and detergent-insoluble glycolipid-enriched membranes (DIGs).

OSMIOPHILIC PATCHES

A form of plasma-membrane heterogeneity that is detected as 'electron-dense' (osmiophilic) areas, which, in mast cells, can be rich in FcɛRI and some signalling molecules.

ITIM

(Immunoreceptor tyrosine-based inhibitory motif). The cytoplasmic sequence — I/VxYxxL —that is present in various inhibitory immunoreceptors, such as FcγRIIB, gp49B1, PIRB and MAFA, is required and sufficient for their inhibitory action by recruiting SHIPs and SHPs through SH2–phosphotyrosine interactions.

ACTIVE CUTANEOUS ANAPHYLAXIS

A skin inflammatory response induced by the injection of antigen in subjects who have undergone active immunization with antigen, instead of passive priming with IgE.

PASSIVE CUTANEOUS ANAPHYLAXIS

An inflammatory response that can be elicited within minutes of antigen challenge in IgE-primed (and, in the mouse, IgG1-primed) skin.

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Kawakami, T., Galli, S. Regulation of mast-cell and basophil function and survival by IgE. Nat Rev Immunol 2, 773–786 (2002). https://doi.org/10.1038/nri914

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