Mechanisms of Eosinophilia in the Pathogenesis of Hypereosinophilic Disorders

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The increased numbers of activated eosinophils in the blood and tissues that typically accompany hypereosinophilic disorders result from a variety of mechanisms. Exciting advances in translating discoveries achieved from mouse models and molecular strategies to the clinic have led to a flurry of new therapeutics specifically designed to target eosinophil-associated diseases. So far, this form of hypothesis testing in humans in vivo through pharmacology generally has supported the paradigms generated in vitro and in animal models, raising hopes that a spectrum of novel therapies soon may become available to help those who have eosinophil-associated diseases.

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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

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    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.

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