Eosinophils

Eosinophils are distinguished from other leukocytes by their morphology, constituent products, and association with specific diseases. Eosinophils are nondividing, fully differentiated cells with a diameter of approximately 8 µm and a bilobed nucleus. They differentiate from stem cell precursors in the bone marrow under the control of T-cell–derived interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and especially IL-5. Their characteristic membrane-bound specific granules stain bright pink with eosin and consist of a crystalline core made up of major basic protein (MBP) surrounded by a matrix containing the eosinophil cationic protein (ECP), eosinophil peroxidase (EPX), and eosinophil-derived neurotoxin (EDN). These basic proteins are cytotoxic for the larval stages of helminthic parasites and are also thought to contribute to much of the inflammation associated with chronic allergic diseases such as asthma (see Chapter 169 ).

Eosinophil MBP, ECP, and EPX are also present in large quantities in the airways of patients who have died of asthma and are thought to inflict epithelial cell damage leading to airway hyperresponsiveness, although recent studies indicate the role of these granule proteins may be more nuanced and not purely destructive. Eosinophil granule contents also contribute to eosinophilic endomyocardial disease associated with the hypereosinophilic syndrome. MBP has the potential to activate other proinflammatory cells, including mast cells, basophils, neutrophils, and platelets. Eosinophils have the capacity to generate large amounts of the lipid mediators platelet-activating factor and leukotriene C ₄ , both of which can cause vasoconstriction, smooth muscle contraction, and mucus hypersecretion ( Fig. 155.1 ). Eosinophils are a source of a number of proinflammatory cytokines, including IL-1, IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF. They have also been shown to influence T-cell recruitment and immune polarization in inflammatory settings. Thus, eosinophils have considerable potential to initiate and sustain the inflammatory response of the innate and acquired immune systems.

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Schematic diagram of an eosinophil and its diverse properties.

Eosinophils are bilobed granulocytes that respond to diverse stimuli, including allergens, helminths, viral infections, allografts, and nonspecific tissue injury. Eosinophils express the receptor for IL-5, a critical eosinophil growth and differentiation factor, as well as the receptor for eotaxin and related chemokines (CCR3). The secondary granules contain four primary cationic proteins designated eosinophil peroxidase (EPO), major basic protein (MBP), eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN). All 4 proteins are cytotoxic molecules; also, ECP and EDN are ribonucleases. In addition to releasing their preformed cationic proteins, eosinophils can release a variety of cytokines, chemokines and neuromediators and generate large amounts of LTC4. Lastly, eosinophils can be induced to express MHC class II and co-stimulatory molecules and may be involved in propagating immune responses by presenting antigen to T cells.

(From Leung YM, Szefler SJ, Bomilla FA, Akdis CA, Sampson HA: Pediatric allergy principles and practice, ed 3, Philadelphia, 2016, Elsevier, p 42.)

Eosinophil migration from the vasculature into the extracellular tissue is mediated by the binding of leukocyte adhesion receptors to their ligands or counterstructures on the postcapillary endothelium. Similar to neutrophils (see Fig. 153.2 ), transmigration begins as the eosinophil selectin receptor binds to the endothelial carbohydrate ligand in loose association, which promotes eosinophils rolling along the endothelial surface until they encounter a priming stimulus such as a chemotactic mediator. Eosinophils then establish a high-affinity bond between integrin receptors and their corresponding immunoglobulin-like ligand. Unlike neutrophils, which become flattened before transmigrating between the tight junctions of the endothelial cells, eosinophils can use unique integrins, known as very late antigens (VLA-4), to bind to vascular cell adhesion molecule (VCAM)-1, which enhances eosinophil adhesion and transmigration through endothelium. Eosinophils are recruited to tissues in inflammatory states by a group of chemokines known as eotaxins (eotaxin 1, 2, and 3). These unique pathways account for selective accumulation of eosinophils in allergic and inflammatory disorders. Eosinophils normally dwell primarily in tissues, especially tissues with an epithelial interface with the environment, including the respiratory, gastrointestinal (GI), and lower genitourinary tracts. The life span of eosinophils may extend for weeks within tissues.

IL-5 selectively enhances eosinophil production, adhesion to endothelial cells, and function. Considerable evidence shows that IL-5 has a pivotal role in promoting eosinophilpoeisis. It is the predominant cytokine in allergen-induced pulmonary late-phase reaction, and antibodies against IL-5 (mepolizumab, reslizumab, benralizumab), decrease sputum eosinophils and reduce exacerbations in a subset of patients with asthma. Eosinophils also bear unique receptors for several chemokines, including RANTES (regulated on activation, normal T-cell expressed and secreted), eotaxin, and monocyte chemotactic proteins 3 and 4. These chemokines appear to be key mediators in the induction of tissue eosinophilia.