New millennium: The conquest of allergy
Mechanisms of eosinophil-associated inflammation☆,☆☆,★

https://doi.org/10.1067/mai.2000.105712Get rights and content

Abstract

Increasing evidence supports a critical role for the eosinophil in disease. Here, the mechanisms underlying eosinophil-associated inflammation are reviewed including eosinophil constituents, eosinophil maturation and release from the bone marrow, and eosinophil tissue recruitment and activation. Eosinophil effector functions in bronchial asthma are summarized with particular attention to pulmonary M2 muscarinic receptors and bronchial hyperreactivity. Recent findings supporting roles for IL-5, the eosinophil, and its ribonucleases in viral immunity are presented. Overall, this information supports an expanded view of eosinophil participation in health and disease. (J Allergy Clin Immunol 2000;105:651-63.)

Section snippets

EOSINOPHIL CONSTITUENTS

Tables I and II list eosinophil-derived products including granule proteins, newly synthesized mediators such as leukotriene C4, oxygen metabolites, and cytokines.

MATURATION OF EOSINOPHILS IN THE BONE MARROW

Eosinophils develop and mature in the bone marrow from IL-5–responsive CD34+ precursor cells (Fig 1).

. Eosinophil maturation in bone marrow. After allergen-induced late-phase reaction, CD34+ cells express IL-5 receptor α-chain. IL-5 drives the CD34+ and IL-5 receptor α-chain+ cells to eosinophil maturation. Under the stimulus of IL-5 or eotaxin, these mature cells shed L-selectin and migrate from the bone marrow to the blood.

CD34+, a cell surface sialomucin-like glycoprotein, specifically marks

EOSINOPHIL TISSUE RECRUITMENT

Eosinophils selectively infiltrate diseased tissues, and recent studies have provided considerable insight into the molecular mechanisms of recruitment. Fig 2 summarizes the steps in this process.

. Schematic summary of eosinophil recruitment to and activation in bronchial tissues. At 1 , the eosinophil is moving in the peripheral blood. At 2 , the eosinophil has tethered to the vessel wall by adhesion molecules (for example, endothelial P-selectin and eosinophil very late activation antigen

EOSINOPHIL CHEMOATTRACTANTS

Since the discovery of eotaxin as an eosinophil chemoattractant in a guinea pig model of asthma,29 murine and human eotaxin have been described.25, 30 Considerable new information highlights the importance of eotaxin in disease. For example, eotaxin is constitutively expressed at high levels in the normal human large and small bowel (where eosinophils normally reside)31 and is up-regulated in ulcerative colitis and lesions of Crohn’s disease.30 Expression of eotaxin mRNA in endothelial cells,

EOSINOPHIL ACTIVATION

Once the eosinophil has migrated into an inflamed tissue, it becomes activated and releases mediators (see Table I, Table II). The activators and regulators of eosinophil function have been reviewed in detail elsewhere.2 Numerous stimuli, including Ig receptors (especially for secretory IgA [sIgA] and IgG), as well as cytokines (such a IL-5, GM-CSF, and IL-3), potently activate the eosinophil and likely participate in eosinophil-associated diseases. Although the high-affinity receptor for IgE,

EOSINOPHIL EFFECTOR FUNCTIONS

Considerable evidence supports the eosinophil’s ability to inflict tissue damage in bronchial asthma,56 and Fig 3 summarizes these mechanisms.

. Proposed role of eosinophils in bronchial asthma. Bronchus, top right , shows a normal portion; top left , epithelial damage resulting from toxic eosmophil granule proteins; bottom left , edematous airway with smooth muscle hyperplasia. X , Halide anions, such as Cl–, Br–, or I–. (Modified from Gleich GJ, Adolphson CR. The eosinophil and bronchial asthma:

BRONCHIAL HYPERREACTIVITY AND MBP

Considerable evidence supports the ability of eosinophil granule MBP to induce bronchial hyperreactivity (BHR), one of the defining criteria of bronchial asthma. First, BHR is significantly correlated with peripheral blood eosinophilia in patients with asthma, both atopic and nonatopic.56 Second, investigations of patients with bronchial asthma showed significant correlations between the percent of BAL eosinophils and BHR, as measured by methacholine PC20 and between the quantities of

BHR AND M2 MUSCARINIC RECEPTOR FUNCTION

The possibility that excessive activity of the cholinergic nerves contributes to the pathophysiologic mechanisms of bronchial asthma is supported by numerous observations, including an early treatment of asthma by inhaling smoke from the stramonium plant containing atropine.68 Acetylcholine released onto M3 muscarinic receptors causes bronchoconstriction.69 Normally, the release of acetylcholine from parasympathetic nerves is inhibited by prejunctional M2 muscarinic receptors on the nerves. The

EOSINOPHILS AND VIRAL INFECTIONS

Viral respiratory tract infections are an important cause of asthma exacerbations.79 Infection with respiratory syncytial virus (RSV) is especially important in infancy. In addition, rhinoviruses are a major cause of asthma exacerbations in school-aged children. Viral infections enhance mediator release during the immediate reaction to antigen and increase recruitment of eosinophils to the lung after antigen challenge.80 The mechanisms by which rhinoviruses enhance airway inflammation are not

CLINICAL HORIZONS

Better methods to appraise eosinophil participation in disease are needed. MBP levels are a useful indicator of eosinophil degranulation, but normal serum or plasma contains appreciable and variable MBP concentrations (likely in the form of proMBP). Thus detection of a modest elevation of MBP is often problematic. Although measurement of ECP in biologic fluids is useful, ECP and EDN are present in neutrophils.103 Therefore fluids from neutrophil-rich lesions could show elevated levels of these

Acknowledgements

I thank Ms Linda Arneson for secretarial assistance, Ms Cheryl Adolphson for editorial assistance, and Drs Hirohito Kita and K. M. Leiferman for critical reading of this manuscript. I hold patents for the use of polyanions as therapies and for treatment of eosinophil-associated diseases with topical anesthetics.

References (111)

  • AF Roffel et al.

    Muscarinic M3 receptors mediate contraction of human central and peripheral airway smooth muscle

    Pulm Pharmacol

    (1990)
  • AD Fryer et al.

    Effects of inflammatory cells on neuronal M2 muscarinic receptor function in the lung

    Life Sci

    (1999)
  • WW Busse et al.

    Viruses in asthma

    J Allergy Clin Immunol

    (1997)
  • KJ Hamann et al.

    Sequence of human eosinophil-derived neurotoxin cDNA: identity of deduced amino acid sequence with human nonsecretory ribonucleases

    Gene

    (1989)
  • KJ Hamann et al.

    Structure and chromosome localization of the human eosinophil-derived neurotoxin and eosinophil cationic protein genes: evidence for intronless coding sequences in the ribonuclease gene superfamily

    Genomics

    (1990)

  • Bronchial asthma

  • H Kita et al.

    Biology of eosinophils

  • R Sehmi et al.

    Allergen-induced increases in IL-5 receptor α-subunit expression on bone marrow–derived CD34+ cells from asthmatic subjects: a novel marker of progenitor cell commitment towards eosinophilic differentiation

    J Clin Invest

    (1997)
  • FJ Herndon et al.

    Depletion of eosinophils by anti-IL-5 monoclonal antibody treatment of mice infected with Trichinella spiralis does not alter parasite burden or immunologic resistance to reinfection

    J Immunol

    (1992)
  • A Sher et al.

    Interleukin 5 is required for the blood and tissue eosinophilia but not granuloma formation induced by infection with Schistosoma mansoni

    Proc Natl Acad Sci U S A

    (1990)
  • RL Barker et al.

    Acidic precursor revealed in human eosinophil granule major basic protein cDNA

    J Exp Med

    (1988)
  • P Popken-Harris et al.

    Expression, purification, and characterization of the recombinant proform of eosinophil granule major basic protein

    J Immunol

    (1995)
  • RT Palframan et al.

    Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by interleukin 5: the role of specific adhesion molecules and phosphatidylinositol 3-kinase

    J Exp Med

    (1998)
  • Y-K Kim et al.

    Immunolocalization of CD34 in nasal polyposis: effect of topical corticosteroids

    Am J Respir Cell Mol Biol

    (1999)
  • SD Robinson et al.

    Multiple, targeted deficiencies in selectins reveal a predominant role for P-selectin in leukocyte recruitment

    Proc Natl Acad Sci U S A

    (1999)
  • BS Bochner et al.

    Differences between human eosinophils and neutrophils in the function and expression of sialic acid–containing counterligands for E-selectin

    J Immunol

    (1994)
  • P Sriramarao et al.

    E-selectin preferentially supports neutrophil but not eosinophil rolling under conditions of flow in vitro and in vivo

    J Immunol

    (1996)
  • A Dobrina et al.

    Mechanisms of eosinophil adherence to cultured vascular endothelial cells: eosinophils bind to the cytokine-induced ligand vascular cell adhesion molecule-1 via the very late activation antigen-4 integrin receptor

    J Clin Invest

    (1991)
  • BS Bochner et al.

    Adhesion of human basophils, eosinophils, and neutrophils to interleukin 1–activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules

    J Exp Med

    (1991)
  • LH Ulfman et al.

    Characterization of eosinophil adhesion to TNF-α–activated endothelium under flow conditions: α4 integrins mediate initial attachment, and E-selectin mediates rolling

    J Immunol

    (1999)
  • MJ Hickey et al.

    Molecular mechanisms underlying IL-4–induced leukocyte recruitment in vivo: a critical role for the α4 integrin

    J Immunol

    (1999)
  • ME Rothenberg et al.

    Murine eotaxin: an eosinophil chemoattractant inducible in endothelial cell and in interleukin 4-induced tumor suppression

    Proc Natl Acad Sci U S A

    (1995)
  • M-J Sanz et al.

    Human eotaxin induces alpha and beta(2) integrin-dependent eosinophil accumulation in rat skin in vivo: delayed generation of eotaxin in response to IL-4

    J Immunol

    (1998)
  • RG DiScipio et al.

    A comparison of C3a and C5a-mediated stable adhesion of rolling eosinophils in postcapillary venules and transendothelial migration in vitro and in vivo

    J Immunol

    (1999)
  • PJ Daffern et al.

    C3a is a chemotaxin for human eosinophils but not for neutrophils, I: C3a stimulation of neutrophils is secondary to eosinophil activation

    J Exp Med

    (1995)
  • PJ Jose et al.

    Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation

    J Exp Med

    (1994)
  • EA Garcia-Zepeda et al.

    Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia

    Nat Med

    (1996)
  • M Kato et al.

    Eosinophil infiltration and degranulation in normal human tissue

    Anat Rec

    (1998)
  • CM Lilly et al.

    Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids

    J Clin Invest

    (1997)
  • B Lamkhioued et al.

    Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes to the chemotaxis of eosinophils to the site of inflammation

    J Immunol

    (1997)
  • O Ghaffar et al.

    Constitutive and cytokine-stimulated expression of eotaxin by human airway smooth muscle cells

    Am J Respir Crit Care Med

    (1999)
  • LM Teran et al.

    Th1- and Th2-type cytokines regulate the expression and production of eotaxin and RANTES by human lung fibroblasts

    Am J Respir Cell Mol Biol

    (1999)
  • M Mochizuki et al.

    IL-4 induces eotaxin: a possible mechanism of selective eosinophil recruitment in helminth infection and atopy

    J Immunol

    (1998)
  • L Li et al.

    Effects of Th2 cytokines on chemokine expression in the lung: IL-13 potently induces eotaxin expression by airway epithelial cells

    J Immunol

    (1999)
  • JR White et al.

    Cloning and functional characterization of a novel human CC chemokine that binds to the CCR3 receptor and activates human eosinophils

    J Leukoc Biol

    (1997)
  • A Shinkai et al.

    A novel human CC chemokine, eotaxin-3, which is expressed in IL-4–stimulated vascular endothelial cells, exhibits potent activity toward eosinophils

    J Immunol

    (1999)
  • I Ohno et al.

    Eosinophils as a source of matrix metalloproteinase-9 in asthmatic airway inflammation

    Am J Respir Cell Mol Biol

    (1997)
  • S Okada et al.

    Transmigration of eosinophils through basement membrane components in vitro: synergistic effects of platelet-activating factor and eosinophil-active cytokines

    Am J Respir Cell Mol Biol

    (1997)
  • S Okada et al.

    Migration of eosinophils through basement membrane components in vitro: role of matrix metalloproteinase-9

    Am J Respir Cell Mol Biol

    (1997)
  • K Kumagai et al.

    Inhibition of matrix metalloproteinases prevents allergen-induced airway inflammation in a murine model of asthma

    J Immunol

    (1999)

    • Cited by (0)

    ☆

    Series editors: Donald Y.M.Leung, MD, PhD, Stanley J. Szefler, MD, and Harold S. Nelson, MD

    ☆☆

    Supported in part by grants from the National Institutes of Health (No. AI 09728 and AI 34577) and from the Mayo Foundation.

    ★

    Reprints not available from the authors.

    View full text
    Copyright © 2000 Mosby, Inc. All rights reserved.