Page 977 - Williams Hematology ( PDFDrive )

952 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 62: Eosinophils and Related Disorders 953

EOSINOPHIL FUNCTIONS Mediator Release
The eosinophil exerts its effects largely through its mediators (see Fig. 62–1). Eosinophils can release a number of lipid mediators and are one of the
These chemicals are either newly generated, as is the case with leukotrienes relatively few sources of suliphidopeptide leukotrienes, although per cell
103
and other lipid mediators, or stored preformed in various compartments they release approximately 10-fold less than mast cells and basophils.
within the cytoplasm and released when the eosinophil receives a degran- This is in contrast to neutrophils that produce large amounts of leu-
ulating stimulus. The eosinophil is relatively biosynthetically inactive and, kotriene (LT)B , but little, if any, LTC . LTC generation by human eosin-
4
4
4
although new protein synthesis does occur, the majority of its protein ophils also occurs after stimulation with opsonized zymosan and beads
mediators are stored. Although the eosinophil can phagocytose particles coated with IgG. Eosinophils can also generate substantial quantities
its interactions with larval forms of helminthic parasites have formed the of 15-HETE (hydroxyeicosatetraenoic acid) via 15-lipoxygenase. Eos-
model by which eosinophil function has been described. In this situation, inophils also generate platelet-activating factor (PAF) after stimulation
the eosinophil adheres tightly to the organism and releases its granule con- with either calcium ionophore or IgG-coated beads. Eosinophils can
tents in local, high concentrations onto the surface in a process described also generate mediators of the cyclooxygenase pathway, including pros-
104
as frustrated phagocytosis. The paradigm of eosinophil effector function in taglandins E and E , thromboxane B (TXB ), and prostaglandin D .
2
2
2
1
2
host defense was developed from the observation that the basic granule pro- The principal sites of eicosanoid formation in eosinophils are the lipid
teins, in particular, were highly toxic for larval parasites. This observation bodies, which contain large amounts of arachidonic acid and enzymes
was extended to include a proinflammatory role in which they were also required for eicosanoid synthesis, including 5-lipoxygenase, LTC syn-
4
105
shown to be toxic for bronchial epithelium and, therefore, associated with thase, and cyclooxygenase. Eosinophils release significant amounts of
the epithelial desquamation which is a well-established feature of severe TGF–β and TGF–α and this has stimulated interest in a potential role
asthma. Eosinophils are not thought to play a major role in bacterial host in causing airway remodeling. There is evidence that TGF–β released
defense and, indeed, bacterial sepsis causes an eosinopenia; however, eosin- by eosinophils can promote the generation of fibromyocytes and anti–
ophils can release mitochondrial DNA which has antibacterial properties. IL-5 reduced the amount of tenascin in the reticular subepithelial
91
Eosinophils can also release a plethora of cytokines and chemokines membrane. 106,107 Thickening of this membrane is closely associated with
although many of these are generated in low amounts compared to other eosinophilic airway inflammation, although not with AHR or airflow
108
cells and the extent to which they are important in eosinophil function is obstruction. Vasoactive intestinal peptide (VIP) has been detected in
not clear. 92 eosinophils in granulomas from mice infected with schistosomes and
the eosinophil contains a number of granule-stored enzymes, whose
Role in Immunoregulation roles in eosinophil function are not clear. These enzymes include acid
Most research into the role of eosinophils has focused on host defense phosphatase, collagenase, arylsulfatase B, histaminase, phospholipase
against helminthic parasites and as effector cells in asthma. How- D, catalase, nonspecific esterases, vitamin B –binding proteins, and
12
ever, since 2010 there has been groundbreaking research emphasiz- glycosaminoglycans. Eosinophils can undergo a respiratory burst with
ing a potential homeostatic role for eosinophils in a number of areas, release of superoxide ion and H O in response to stimulation, with
2
2
including antigen presentation, tissue repair, adipogenesis and glucose both particulate stimuli, such as opsonized zymosan, and soluble medi-
homeostasis, and B-cell development. There has been evidence for ators, such as leukotriene and phorbolmyrisate acetate. Eosinophils are
93
many years that eosinophils can present antigen to T cells, although twice as chemoluminescent as neutrophils.
the physiologic relevance of this function in the context of an intact
dendritic cell antigen-presenting capacity remains uncertain. Type 2 Eosinophil Granule Proteins
94
immunity is necessary for the regeneration of skeletal muscle after A specific and important feature of eosinophils is the large amounts of basic
injury. Muscle damage resulted in the rapid recruitment of eosinophils, proteins they contain within their specific granules. These are MBP, eosin-
which secretes IL-4 and activates muscle resident stem cells. Similarly, ophil cationic protein (ECP), eosinophil peroxidase, and eosinophil derived
95
eosinophil-derived IL-4 was necessary for liver regeneration. A role neurotoxin (EDN). MBP has a molecular mass of 13.8 kDa and an isoelec-
109
96
in adipose tissue and glucose homeostasis was first suggested in 2011 tric point (pI) of 10.9. Its 17 arginine residues account for its alkalinity. It is
when it was demonstrated that eosinophils, through the production of initially synthesized as an acidic proprotein that is stored in the eosinophil
IL-4, were necessary for the maintenance of adipose tissue associated granule. MBP becomes toxic only after it is released and processed into its
alternatively activated macrophages, which, in turn, were necessary to final form. Purified MBP is cytotoxic for the schistosomula of Schistosoma
control glucose metabolism and body fat. This same pathway in con- mansoni, and adherence of eosinophils to IgG-coated schistosomula results
97
cert with ILC2 cells is involved in the development of cold-induced, in the secretion of MBP onto the tegument of the larvae, resulting in loss
110
beige fat, which provides a defense against cold and obesity. 98,99 Long- of viability. MBP at concentrations as low as 10 mg/mL is toxic for both
lived plasma cells, which survive in specialized niches in the marrow, do guinea pig and human respiratory epithelial cells, as well as for rat and
so as a result of growth factors (APRIL and IL-6) supplied by colocalized human pneumocytes. The mechanism of action of MBP on epithelial cells is
eosinophils. Eosinophils are also important in gut immune homeo- mediated through inhibition of adenosine triphosphatase (ATPase) activity.
100
stasis, with eosinophil deficiency resulting in a reduction in IgA plasma MBP and eosinophil peroxidase are strong agonists for platelet activation
+
111
cells and secreted IgA, as well as defects in the intestinal mucous shield, as well as activation of mast cells, basophils, and neutrophils. The mecha-
alteration in the gut microbiota, and the formation of CD103 Tr and nisms of action of MBP is likely to be related to its hydrophobicity and strong
+
dendritic cells. B-cell development was also shown to be regulated negative charge. Basophils also contain MBP but only approximately 2 per-
101
by eosinophils in mice and humans. These studies were almost exclu- cent that of eosinophils.
102
sively undertaken in mice, but they are potentially clinically relevant as Eosinophil peroxidase is a heme-containing protein that is synthe-
a number of biologic therapies targeted at the Th2 pathway, including sized as a single protein and then cleaved into 14- and 58-kDa subunits.
specific antieosinophil therapies, are in the late stages of clinical devel- The molecule shares a 68 percent identity in amino acid sequence
opment for asthma and other eosinophilic diseases. So far, these drugs with human neutrophil myeloperoxidase as well as other peroxidase
appear relatively free of serious adverse effects, so it is possible that the enzymes. The protein is toxic for parasites, respiratory epithelium, and
relatively modest effects of these drugs on the tissue eosinophilia means pneumocytes, either alone, or (more potently) when combined with
that the homeostatic role of eosinophils will not be perturbed. H O and halide, the preferred ion in vivo being bromide.
2
2
Kaushansky_chapter 62_p0947-0964.indd 952 9/21/15 10:56 AM