REGULATION OF THE PRODUCTION AND ACTIVATION OF EOSINOPHILS
Eosinophils are bone marrow–derived cells that circulate transiently and normally account for up to 6% (up to 600/mm3) of circulating blood leukocytes.
Eosinophils primarily are tissue-dwelling cells, but only in certain tissues in humans, with an average tissue life span of 2 to 5 days that may be increased with eosinophil survival factors for up to 14 days.
As proinflammatory cells, the presence of eosinophils within most tissues is associated with pathologic states that include infections, allergic reactions and atopic diseases, fibrotic disorders, reactive eosinophilias, and hypereosinophilic syndromes.
Eosinophils play a role in innate and adaptive immune responses, which may explain why they are present in normal, noninflamed tissues such as the gastrointestinal tract and lymphoid tissues.
This section reviews the biologic actions of eosinophils with particular focus on what controls eosinophil production, activation, and tissue trafficking.
Pharmacologic manipulation of eosinophil inflammation is possible as new, more specific strategies are emerging.
Eosinophils develop in the bone marrow from multipotential, stem cell–derived CD34+ myeloid progenitor cells in response to eosinophilopoietic cytokines and growth factors (Fig. 40-1). They are released into the circulation as mature cells.1-3 Important stimulatory cytokines and growth factors for eosinophils include interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5. Activated T cells likely are the principal sources of IL-3, GM-CSF, and IL-5 that induce eosinophil differentiation in bone marrow. However, depending on pathogenic stimuli, eosinophilopoietic cytokines may be released by other cell types, including mast cells, macrophages, natural killer cells, endothelial cells, epithelial cells, fibroblasts, and even eosinophils, themselves.4 IL-3 and GM-CSF are pluripotent cytokines that have effects on other hematopoietic lineages. IL-5 is the most selective eosinophil-active cytokine, but it is relatively late acting. Although it is both necessary and sufficient for eosinophil differentiation, IL-5 demonstrates maximum activity on the IL-5 receptor (IL-5R)–positive eosinophil progenitor pool that first is expanded by earlier acting pluripotent cytokines such as IL-3 and GM-CSF4; expression of the high-affinity IL-5R is a prerequisite for eosinophil development. Exodus from the bone marrow also is regulated by IL-5. IL-3 and GM-CSF, along with IL-5, promote survival, activation, and chemotaxis of eosinophils through binding to receptors that have a common β chain (CD131) with IL-5R, and unique α chains.
The progression of eosinophils from undifferentiated hematopoietic cells to their fate in tissue. The image depicts the eosinophil’s life from differentiation in the bone marrow to vascular transmigration to its fate in tissue with key factors noted. GM-CSF, granulocyte-macrophage colony-stimulating factor; ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; LTB4, leukotriene B4; TGF, transforming growth factor; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.
INTERACTIONS OF EOSINOPHILIC FACTORS AND CYTOKINES AND INTRACELLULAR SIGNALING