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CHAPTER 62 leukotrienes, as well as other lipid mediators, such as platelet-activating

EOSINOPHILS AND RELATED factor (PAF). Cytokine production by eosinophils broadens their potential
functions, for example in wound healing through their generation of trans-
DISORDERS forming growth factor (TGF)-α. Synthesis of TGF-β may explain the propensity
of eosinophils to be associated with fibrotic reactions such as endomyocardial
fibrosis, characteristic of HES, and fibrosing alveolitis.
Considerable effort has gone into trying to unravel the molecular basis of
Andrew J. Wardlaw eosinophil tissue recruitment. The selective accumulation of eosinophils is the
result of a concerted and integrated series of events involving their production
in the marrow and egress therefrom, adhesion to endothelium, selective che-
SUMMARY motaxis, and prolonged survival in tissues. These events are controlled, either
directly or indirectly, by production of IL-4, IL-5, and IL-13.
Eosinophils continue to be studied intensively, in large part, as a result of their The discovery that a proportion of patients with HES have either a clonal
potential role in the pathogenesis of asthma. The concept of the eosinophil as myeloid neoplasm resulting from an acquired mutation that generates a
a cell that has protective effects against helminthic parasite infection, but can constitutively active, novel tyrosine kinase (FIP1L1-PDGFRα [F/P]) or a T-cell
cause tissue damage when inappropriately activated, remains intact, although lymphoproliferative disease causing a reactive eosinophilia has offered the
the evidence for both these roles is circumstantial. Eosinophil production and prospect of new and more effective treatments for these conditions, as well as
function are profoundly influenced by interleukin (IL)-5; and, thus, eosino- giving new insights into the control of eosinophil production. There has long
philia is associated with diseases characterized by T-helper (Th)2-mediated been a debate about the extent to which eosinophils cause tissue damage, are
immune responses, including infections by helminthic parasites and extrinsic innocent bystanders, or even help to ameliorate the condition. This is now being
asthma. However, eosinophilia also occurs in diseases not obviously associated resolved with data showing that specific reduction in eosinophils using anti–
with Th2 dominance, such as intrinsic asthma, hypereosinophilic syndromes IL-5 monoclonal antibody is beneficial in eosinophilic airway disease and HES.
(HESs), and inflammatory bowel disease. Thus, IL-5 and other eosinophil
mediators can be generated in various types of inflammatory response.
The eosinophil, like other leukocytes, can generate proinflammatory medi-
ators. Eosinophil-specific granule proteins are toxic for a range of mammalian
cells and parasitic larvae. Eosinophils, like mast cells, produce sulfidopeptide BIOLOGY OF EOSINOPHILS
EOSINOPHIL MORPHOLOGY AND
RECEPTOR PHENOTYPE
Eosinophils are spherical, end-stage, nondividing leukocytes,
Acronyms and Abbreviations: AAV, ANCA-associated vasculitides; AHR, approximately 8 μm in diameter derived from the marrow. In vitro
1
airway hyperresponsiveness; ANCA, antineutrophil cytoplasmic antibodies; granulocyte-monocyte colony-stimulating factor (GM-CSF), inter-
BAL, bronchoalveolar lavage; BSA, bovine serum albumin; CCL, chemokine leukin (IL)-3 and IL-5 stimulate colony growth; additionally, IL-5
(C-C motif) ligand; CCR, chemokine receptor; CEL, chronic eosinophilic is a critical eosinopoietic factor in vivo involved in late differenti-
2
leukemia; CLC, Charcot-Leyden crystal; CLM-1, CMRF35-like molecule-1; ation. The electron microscopic (EM) morphology of the mature
3,4
CMPD, chronic myeloproliferative disease; ECP, eosinophil cationic protein; eosinophil has been well described (Fig. 62–1). The relatively spe-
EDN, eosinophil-derived neurotoxin; EGPA, eosinophilic granulomatosis with cific features which distinguish the eosinophil from other leuko-
polyangiitis; EM, electron microscopic; EMR, mucin-like hormone receptor; cytes are the bilobed nucleus, the specific granules with an electron
FEV , forced expiratory volume in 1 second; FISH, fluorescence in situ hybrid- dense core, the paucity of mitochondria (approximately 20 per cell)
1
ization; GM-CSF, granulocyte-monocyte colony-stimulating growth factor; and endoplasmic reticulum, and the dense network of cytoplasmic
tubulovesicular structures or secretory vesicles that contain albu-
GPA, granulomatosis with polyangiitis; HES, hypereosinophilic syndrome; min and cytochrome b and are therefore thought to be involved
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HLA, human leukocyte antigen; ICAM, intercellular adhesion molecule; iHES, in superoxide production. Eosinophils also contain lipid bodies,
idiopathic hypereosinophilic syndrome; IL, interleukin; ILC, innate lymphoid which are the major site of eicosanoid synthesis, primary granules,
cell; LAMP, lysosome-associated membrane protein; LIMP, lysosome integral and small granules. Small granules are particularly prominent in
5
membrane protein; LT, leukotriene; mAb, monoclonal antibody; MBP, major tissue eosinophils and contain arylsulphatase B, acid phosphatase,
basic protein; MPA, microscopic polyangiitis; NADPH, nicotinamide adenine and catalase. They may be derived from specific granules and act
dinucleotide phosphate oxidase; NO, nitric oxide; ORMDL3, orosomucoid- as a lysosomal compartment since specific granules express lys-
like 3; PAF, platelet-activating factor; PIN1, peptidylprolyl isomerase; PSGL, osome-associated membrane proteins (LAMP) 1 and 2, as well as
6
P-selectin glycoprotein ligand; Siglec, sialic acid-recognizing animal lectin; lysosome integral membrane protein (LIMP, CD63) 1. Eosinophils
SNARE, soluble N-ethylmaleimide–sensitive factor attachment protein also contain multilaminar bodies that contain transforming growth
receptor complex; TGF, transforming growth factor; Th, T-helper; TRAIL, factor (TGF)–α. Eosinophil precursors derived from cord blood can
be first identified morphologically when specific core containing
tumor necrosis factor-related apoptosis-inducing ligand; T , T-regulatory granules appear, although expression of Charcot Leyden crystal
REG
cell; TSLP, thymic stromal lymphopoietin; TXB thromboxane B ; VCAM, (CLC) protein and the basic granules proteins can be detected by
2
2,
vascular cell adhesion molecule; VIP, vasoactive intestinal peptide; VLA, immunohistochemistry or mRNA expression at the promyelocyte
very-late antigen; WHO, World Health Organization. stage where they are found in the endoplasmic reticulum, Golgi
apparatus and large round coreless granules, most of which develop

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