Mechanisms of Eosinophilia in the Pathogenesis of Hypereosinophilic Disorders
Section snippets
Cytokine regulation of eosinophilopoiesis in the bone marrow
Eosinophils differentiate in the bone marrow from stem cell-derived, CD34+, multipotential myeloid progenitors in response to a number of T-cell–derived eosinophilopoietic cytokines and growth factors including IL-3, granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-5. These cytokines affect the eosinophil lineage at three different levels: (1) commitment, proliferation, and differentiation of the hematopoietic progenitors; (2) priming, activation, and survival in the blood and
Transcriptional regulation of eosinophil lineage commitment and differentiation
During the past 15 years studies of the mechanisms that regulate myeloid gene transcription, hematopoietic lineage specification, and differentiation have provided novel insights into the roles of combinatorial networks of transcription factors in determining progenitor cell fate, including eosinophil lineage commitment and terminal differentiation. Current findings from avian, mouse, and human studies suggest that a handful of transcription factors and their functional interactions are
Regulation of eosinophil differentiation by cytokines and exit from the bone marrow
Based on studies with anti-IL-5 antibody, it now is clear that IL-5 is critical for terminal eosinophil differentiation [44], [45]. Indeed, one of the key terminal steps in eosinophil hematopoiesis involves surface expression of the IL-5R [46]. Until this point, eosinophils and basophils share maturation pathways. Remnants of these shared differentiation pathways persist even though their divergence is clear when examining their mature circulating counterparts. For example, circulating
Eosinophil trafficking out of the circulation into tissues
Production of IL-5 and/or GM-CSF, as well as administration of these cytokines in humans, results in rapid and sustained peripheral blood eosinophilia [63], [64]. Once in the circulation, eosinophils persist there for 18 to 24 hours before migrating to extravascular sites. This circulation time may be even longer in conditions associated with peripheral blood eosinophilia. Diseases associated with eosinophilia, such as hypereosinophilic syndromes, frequently, but not always, are associated with
Activation of eosinophil degranulation and mediator release
For eosinophils to participate in local tissue pathobiology, more must occur than their accumulation; indeed, activation of recruited eosinophils is thought to be a critical aspect of disease pathophysiology. For example, IL-5–transgenic mice have massively increased numbers of eosinophils in the circulation, spleen, and other tissues, but without a second signal these mice are relatively healthy. One of the major pathways by which eosinophils are activated is through cross-linking of surface
Regulation of tissue eosinophil survival and activation
Once in tissues, if eosinophils do not encounter the appropriate survival milieu, the lack of exposure to such cytokines normally leads to their prompt apoptosis (see Fig. 2). Separate from this process, however, a number of pathways actively and, to varying degrees, selectively induce eosinophil apoptosis. In humans, corticosteroids markedly and rapidly diminish numbers of circulating and tissue eosinophils. The mechanisms responsible for this action are complex and probably involve a
Summary
The heterogeneity of hypereosinophilic syndromes, which ranges from patients who have features of myeloproliferative disorders with cytogenetic abnormalities (eg, FIP1L1-PDGFRα–positive chronic eosinophil leukemia, CEL) to patients who have more benign clinical courses (eg, episodic angioedema with eosinophilia), suggests that multiple disease processes are at play that regulate eosinophilopoiesis in the bone marrow, the recruitment of eosinophils to tissues and their survival, the activation
References (154)
The role of eosinophils in the pathogenesis of asthma
Trends Mol Med
(2005)- et al.
A role for eosinophils in airway remodelling in asthma
Trends Immunol
(2004) - et al.
Eosinophil-fibroblast interactions induce fibroblast IL-6 secretion and extracellular matrix gene expression: implications in fibrogenesis
J Allergy Clin Immunol
(2005) - et al.
Intravenous anti-IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin
J Invest Dermatol
(2004) - et al.
Anti-IL-5 (Mepolizumab) therapy for eosinophilic esophagitis
J Allergy Clin Immunol
(2006) - et al.
Steroid-sparing effects of anti-IL-5 monoclonal antibody (Mepolizumab) therapy in patients with HES: a multicenter, randomized, double-blind, placebo-controlled trial
Blood [ASH Annual Meeting Abstracts]
(2006) Interleukin-5, eosinophils, and disease
Blood
(1992)- 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) - et al.
Hematopoietic development: a balancing act
Curr Opin Genet Dev
(2001) - et al.
C/EBPbeta and GATA-1 synergistically regulate activity of the eosinophil granule major basic protein promoter: implication for C/EBPbeta activity in eosinophil gene expression
Blood
(1999)
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
Neutrophil-specific granule deficiency includes eosinophils
Blood
Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome
Blood
Anti-IL-5 (Mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics
J Allergy Clin Immunol
Human interleukin-5 (IL-5) regulates the production of eosinophils in human bone marrow cultures: comparison and interaction with IL-1, IL-3, IL-6, and GMCSF
Blood
Blood eosinophils from atopic donors express messenger RNA for the alpha, beta, and gamma subunits of the high-affinity IgE receptor (Fc epsilon RI) and intracellular, but not cell surface, alpha subunit protein
J Allergy Clin Immunol
Molecular analysis of human Siglec-8 orthologs relevant to mouse eosinophils: identification of mouse orthologs of Siglec-5 (mSiglec-F) and Siglec-10 (mSiglec-G)
Genomics
Identification of SAF-2, a novel Siglec expressed on eosinophils, mast cells and basophils
J Allergy Clin Immunol
Eotaxin induces a rapid release of eosinophils and their progenitors from the bone marrow
Blood
Episodic eosinophilia-myalgia-like syndrome in a patient without L-tryptophan use: association with eosinophil activation and increased serum levels of granulocyte-macrophage colony-stimulating factor
J Allergy Clin Immunol
Elevated serum levels of interleukin-5 in patients with the syndrome of episodic angioedema and eosinophilia
Blood
Increased circulating levels of interleukin-5 in a case of steroid-resistant hypereosinophilic syndrome with ileal involvement
J Allergy Clin Immunol
Adhesion molecules as therapeutic targets
Immunol Allergy Clin North Am
The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma
J Allergy Clin Immunol
Leptin is an eosinophil survival factor
J Allergy Clin Immunol
CD40 engagement enhances eosinophil survival through induction of cellular inhibitor of apoptosis protein 2 expression: possible involvement in allergic inflammation
J Allergy Clin Immunol
Systemic aspects of chronic rhinosinusitis
Immunol Allergy Clin North Am
Cytokines in symptomatic asthma airways
J Allergy Clin Immunol
Blood and bronchoalveolar eosinophils in allergic subjects following segmental antigen challenge: surface phenotype, density heterogeneity, and prostanoid production
J Allergy Clin Immunol
Eosinophil trafficking in allergy and asthma
J Allergy Clin Immunol
Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma
J Allergy Clin Immunol
Expression of a functional laminin receptor (a6b1, VLA-6) on human eosinophils
Blood
Road signs guiding leukocytes along the inflammation superhighway
J Allergy Clin Immunol
Molecular basis for selective eosinophil trafficking in asthma: a multistep paradigm
J Allergy Clin 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
Defining a link with asthma in mice congenitally deficient in eosinophils
Science
A critical role for eosinophils in allergic airways remodeling
Science
Anti-IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics
J Clin Invest
T cell-replacing factor (TRF)/interleukin 5 (IL-5): molecular and functional properties
Immunol Rev
Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores
Nature
Mast cell and eosinophil cytokines in allergy and inflammation
Ly1+ PRO-B lymphocyte clones. Phenotype, growth requirements and differentiation in vitro and in vivo
EMBO J
Signal transduction through interleukin-5 receptors
Cold Spring Harb Symp Quant Biol
Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors
J Exp Med
Eosinophil differentiation factor (interleukin-5)
Immunol Ser
Control of eosinophilia
Int Arch Allergy Appl Immunol
Interleukin 5 and phenotypically altered eosinophils in the blood of patients with the idiopathic hypereosinophilic syndrome
J Exp Med
Hypodense eosinophils and interleukin 5 activity in the blood of patients with the eosinophilia-myalgia syndrome
Proc Natl Acad Sci U S A
Eosinophilia in transgenic mice expressing Interleukin-5
J Exp Med
Transgenic mice expressing a B-cell growth and differentiation factor gene (interleukin-5) develop eosinophilia and autoantibody production
J Exp Med
Cited by (0)
This work was supported in part by grants AI033043 (to SJA) and AI041472 (to BSB) from the National Institutes of Health. Dr. Bochner also received support as a Cosner Scholar in Translational Research from Johns Hopkins University.