Reviews and feature articlesEosinophil trafficking in allergy and asthma
Section snippets
A caveat on human versus mouse eosinophils
It is important to recognize that most of the findings to be discussed result from work performed in mouse models of disease. Although all investigations can suffer from overinterpretation of cross-species findings,11, 12 the problems are particularly large when examining results related to the eosinophil. Although mouse eosinophils, like human eosinophils, can be identified by red-staining granules in blood, bone marrow, and tissue preparations stained either with hematoxylin and eosin or
Eosinophil expansion in response to allergic provocation
An allergic response is initiated in situ as a CD4+ naive T lymphocyte responds to specific stimulation by developing into a TH2 lymphocyte. TH2 lymphocytes synthesize and secrete the cytokines IL-4, IL-13, and IL-5. IL-4 promotes eosinophilia indirectly via promoting autocrine development of TH2 lymphocytes, and murine eosinophils themselves produce IL-4.19, 20 Human eosinophils express IL-4 receptor α (IL-4Rα).21, 22 IL-4 also activates human vascular endothelial and respiratory epithelial
The pivotal role of IL-5
The TH2 cytokine IL-5 is a central factor mediating eosinophil expansion, priming, recruitment, and prolonged tissue survival in response to allergic stimuli. Originally identified as murine T-cell replacing factor, a B-cell growth factor and eosinophil differentiation factor, IL-5 is synthesized predominantly by TH2 lymphocytes, but in smaller amounts by mast cells and eosinophils. IL-5 promotes differentiation of terminally committed human and murine eosinophil precursors in bone marrow.28, 29
Eosinophil development in the bone marrow
Committed eosinophil progenitors are derived from pluripotent CD34+ stem cells found in normal bone marrow. Of note, committed CD34+IL-5R+ eosinophil progenitor cells have also recently been identified in murine lung tissue.34 Studies of ex vivo bone marrow cultures have shown that eosinophils develop from these progenitors in response to GM-CSF, IL-3, and IL-5. When they are phenotypically mature, eosinophils are released from the bone marrow into the circulation.
As noted, IL-5 is a strong and
Eosinophil transit into tissues
Mature eosinophils leave the bone marrow and are attracted to sites of allergic inflammation by the actions of proinflammatory chemokines, which are produced in response to allergic stimulation by endothelial and epithelial cells activated by, among other mediators, IL-4 and IL-13. Eosinophils express receptors for the CC group of chemokines (those that contain adjacent cysteines near the amino terminus). Several CC chemokines have been characterized as eosinophil chemoattractants, including
Eosinophil survival and apoptosis
A final aspect of eosinophil trafficking involves its survival and functioning within peripheral tissues. There are several excellent reviews that detail general findings relating to apoptosis signaling pathways described in eosinophils.74, 75, 76 Among the findings that relate uniquely to the biology of eosinophils, IL-5 clearly promotes eosinophil survival in vitro, and the absence of IL-5 results in spontaneous cellular apoptosis. Simon et al76 and Simon77 have shown that IL-5 is also
Clinical implications
Given the pivotal role of IL-5, it seemed reasonable to assume that blockade of IL-5 would result in the elimination of eosinophilia and thus the reduction in symptomatology associated with allergic asthma. This hypothesis was tested in clinical trials using 2 humanized monoclonal anti–IL-5 antibodies, SCH55700 (Schering-Plough Research Institute, Kenilworth, NJ) and mepolizumab (GlaxoSmithKline, Middlesex, United Kingdom). In a randomized, double-blind study of mepolizumab, clinical symptoms
Conclusion and future directions
Despite some controversial findings, the balance of data suggests that eosinophils promote 1 or more aspects of respiratory dysfunction characteristic of allergic asthma. As such, the possibility that drugs directed at inhibition of eosinophil migration or activation or even outright eosinophil ablation might prove to be effective therapeutic strategies certainly remains worthy of further exploration. Among the avenues that might be considered is the possibility that coordinate inhibition of
References (111)
- et al.
The role of eosinophils in host defense against helminth parasites
J Allergy Clin Immunol
(2004) - et al.
The role of eosinophils in parasitic helminth infections: insights from genetically modified mice
Parasitol Today
(2000) - et al.
Allergy and asthma
J Allergy Clin Immunol
(2005) Mechanisms of the hygiene hypothesis: molecular and otherwise
Curr Opin Immunol
(2006)- et al.
Renaissance of the hygiene hypothesis
J Allergy Clin Immunol
(2006) Of mice and men: species variations of Toll-like receptor expression
Trends Immunol
(2002)- et al.
Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production
Immunity
(2004) Anti-interleukin-4 therapy
Immunol Allergy Clin North Am
(2004)- et al.
Systemic aspects of allergic disease: bone marrow responses
J Allergy Clin Immunol
(2000) - et al.
IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses
Immunity
(1996)
Novel combinatorial interactions of GATA-1, PU.1, and C/EBPepsilon isoforms regulate transcription of the gene encoding eosinophil granule major basic protein
J Biol Chem
Regulation of neutrophil and eosinophil secondary granule gene expression by transcription factors C/EBP epsilon and PU.1
Blood
Eotaxin-3/CCL26 gene expression in intestinal epithelial cells is up-regulated by interleukin-4 and interleukin-13 via the signal transducer and activator of transcription 6
Int J Biochem Cell Biol
IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism
J Allergy Clin Immunol
Eosinophilic gastrointestinal disorders (EGID)
J Allergy Clin Immunol
Eotaxin modulates myelopoiesis and mast cell development from embryonic hematopoietic progenitors
Blood
Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow
Blood
Eotaxin-2 and IL-5 cooperate in the lung to regulate IL-13 production and airway eosinophilia and hyperreactivity
J Allergy Clin Immunol
Identification of a cooperative mechanism involving inerleukin-13 and eotaxin-2 in experimental allergic lung inflammation
J Biol Chem
Eotaxin-3 and interleukin-5 pleural fluid levels are associated with pleural fluid eosinophilia in post-coronary artery bypass grafting pleural effusions
Chest
Eosinophilic esophagitis: pathogenesis, genetics, and therapy
J Allergy Clin Immunol
Variant eotaxin: its effects on the asthma phenotype
J Allergy Clin Immunol
Analysis of the polymorphisms in eotaxin gene family and their association with asthma, IgE, and eosinophil
Biochem Biophys Res Commun
Eotaxin induces a sustained reduction in the functional adhesive state of very late antigen 4 for the connecting segment 1 region of fibronectin
J Allergy Clin Immunol
The effect of anti-integrin monoclonal antibodies on antigen-induced pulmonary inflammation in allergic rabbits
Pulm Pharmacol Ther
Inhibition of eosinophilia in vivo by a small molecule inhibitor of very late antigen (VLA)-4
Eur J Pharmacol
Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma
J Allergy Clin Immunol
Sulfated L-selectin ligands as a therapeutic target in chronic inflammation
Trends Immunol
Bimosiamose, an inhaled small-molecule pan-selectin antagonist, attenuates late asthmatic reactions following allergen challenge in mild asthmatics: a randomized, double-blind, placebo-controlled clinical cross-over-trial
Pulm Pharmacol Ther
Dexamethasone inhibits prolonged survival and autocrine granulocyte-macrophage colony-stimulating factor production by human eosinophils cultured on laminin or tissue fibronectin
J Allergy Clin Immunol
Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis
Blood
Mechanism of Siglec-8-induced human eosinophil apoptosis: role of caspases and mitochondrial injury
Biochem Biophys Res Commun
Anti-interleukin-5 therapy for asthma and hypereosinophilic syndrome
Immunol Allergy Clin North Am
The trials and tribulations of IL-5, eosinophils, and allergic asthma
J Allergy Clin Immunol
Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin
J Invest Dermatol
The Hypereosinophilic Syndromes Working Group. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report
J Allergy Clin Immunol
The eosinophil
Annu Rev Immunol
Eosinophil trafficking in asthma
Clin Med
Neutrophils and eosinophils: clinical implications of their appearance, presence and disappearance in asthma and COPD
Curr Drug Targets Inflamm Allergy
Corticosteroids, eosinophils and bronchial epithelial cells: new insights into the resolution of inflammation in asthma
J Endocrinol
The hygiene hypothesis and asthma
Curr Opin Pulm Med
Of mice and not men: differences between mouse and human immunology
J Immunol
The eosinophil ribonucleases
Cell Mol Life Sci
The murine inhibitory receptor mSiglec-E is expressed broadly on cells of the innate immune system whereas mSiglec-F is restricted to eosinophils
Eur J Immunol
Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils
Blood
Molecular diversity and evolution of the Siglec family of cell-surface lectins
Mol Divers
In vitro assessment of chemokine receptor-ligand interactions mediating mouse eosinophil migration
J Leukoc Biol
Eosinophil degranulation: an evolutionary vestige or a universally destructive effector function?
Clin Exp Allergy
Mast cells, basophils, and eosinophils acquire constitutive IL-4 and IL-13 transcripts during lineage differentiation that are sufficient for rapid cytokine production
J Immunol
IL-4-dependent regulation of TGF-alpha and TGF-beta1 expression in human eosinophils
J Immunol
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(Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)
Series editors: Joshua A. Boyce, MD, Fred Finkelman, MD, William T. Shearer, MD, PhD, and Donata Vercelli, MD
Disclosure of potential conflict of interest: S. Phipps has received grant support from the Australian Lung Foundation. H. F. Rosenberg and P. S. Foster have declared that they have no conflict of interest.