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950 Part VII: Neutrophils, Eosinophils, Basophils, and Mast Cells Chapter 62: Eosinophils and Related Disorders 951

Many eosinophilic diseases, including many cases of pulmonary general inflammatory response, as for example in idiopathic pulmo-
eosinophilia, are not associated with atopy and IgE production and nary fibrosis where increased numbers of eosinophils and neutrophils
therefore do not entirely fit with the Th2-driven eosinophilic paradigm. can be seen in the BAL fluid, it often occurs without a marked increase
Intrinsic asthma is generally assumed to be associated with IL-5- in other leukocytes raising the question of the mechanism behind the
producing T cells; however, the evidence for this is limited. One model specific tissue accumulation of these picturesque leukocytes. Selective
for non–IgE-associated eosinophilic disease is those cases of eosino- eosinophil accumulation occurs as a result of the coordinated effect of
philic esophagitis caused by a defined food allergen in which there is no a number of adhesion, chemotactic and growth/survival orientated sig-
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specific IgE. In some of these cases, the patients are patch-test–positive nals at each stage in the life cycle of the cell. Generally speaking, these
to the food allergen concerned, which raises the possibility of a Th2 type events are controlled by mediators associated with Th2 cells, in par-
of type IV cell-mediated immunity, but this is still unexplored. ticular the cytokines IL-4, IL-5, IL-13, and possibly IL-9. 57,58 Another
There is increasing interest in the role of T regulatory cells (T REG ) in group of epithelial derived cytokines—IL-25, IL-33, and thymic stromal
controlling inappropriate immune responses including those associated lymphopoietin (TSLP)—play a key role in the development of eosino-
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with Th2 cell activation. T REG were first identified as mediating some philic inflammation through the activation of a newly described class of
aspects of immune tolerance and were then found to play an impor- innate immune cells called ILC2. 59
tant role in suppressing immune-mediated inflammatory bowel disease As well as being crucial for differentiation, IL-5 is also important in
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in mice. Three types of T REG cells have been identified: CD4 /CD25 promoting emigration from the marrow. In particular, it acts as a prim-
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cells which require direct contact to mediate their immunosuppressive ing factor for specific chemoattractants such as eotaxin. The observa-
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effects, T REG cells producing TGF-β and T REG cells producing IL-10. 46–48 tion that eotaxin decreased adhesion to vascular cell adhesion molecule
A current idea is that the increase in allergic disease that is also par- (VCAM)-1 while increasing adhesion to the CD18 ligand bovine serum
alleled by an increase in autoimmune disease is not caused by a Th1 albumin (BSA) may be a mechanism for promoting egress from the
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to Th2 switch, but by a failure to develop T REG responses, which leads marrow. Localized inflammatory responses can cause systemic effects
to enhancement of both Th1 and Th2 immunity. 49–51 IL-10 producing after allergen challenge in mice in which IL-5–producing cells (both
T REG is of particular interest in the context of pulmonary eosinophilia T cells and non–T cells), increase in the marrow. 62
because of evidence that immunotherapy works by inducing expansion Accumulation of leukocytes in tissue is a highly regulated process
of an antigen specific IL-10 producing T REG cells. In addition, regu- with the aim of being able to respond effectively to noxious insults with-
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latory T cells were able to suppress ovalbumin-induced pulmonary out causing an inappropriate inflammatory response. An obligate step in
eosinophilia in mice. 53 the migration of all leukocytes from the systemic circulation into tissue
is their capture by endothelium as they flow at high shear rates through
EOSINOPHIL HETEROGENEITY the postcapillary endothelium. A key receptor mediating eosinophil
capture is P-selectin, whose low-level surface expression is selectively
Blood eosinophils from normal individuals are relatively dense cells that induced on endothelium by IL-4 and IL-13. Eosinophils express higher
can be separated from other leukocytes by density-gradient centrifuge. levels of P-selectin glycoprotein ligand (PSGL)-1 (the primary receptor
For many years these differences were the basis for the standard method for P-selectin) than other leukocytes and this results in increased avidity
of purifying eosinophils. This method has now been largely superseded for P-selectin compared to neutrophils, especially at the low levels of
by negative immunomagnetic selection based on the expression of the expression induced by Th2 cytokines. Increased expression of PSGL-1
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low affinity (Fcγ RIII, CD16) IgG receptor by neutrophils but not eos- leading to enhanced recruitment has also been reported in allergic
inophils. This latter technique has the advantage of improved purity disease. IL-4 and IL-13 can also induce low levels of VCAM-1 expres-
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and cell yields as well as enabling purification of eosinophils from indi- sion which can bind eosinophils through very-late antigen (VLA)-4
viduals with low eosinophil counts, A proportion of eosinophils from and also capture flowing cells albeit at lower shear stresses. VLA-4/
individuals with elevated eosinophil counts are less dense than eosin- VCAM-1 and PSGL-1/P-selectin cooperate as a major endothelial con-
ophils from normal subjects. So-called hypodense eosinophils appear trol point for selective eosinophil migration. Once captured, eosino-
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to be vacuolated and contain smaller granules, although in equal num- phils roll along the surface of the blood vessel until they are activated,
bers to normal-density eosinophils. The mechanism for this heteroge- which allows the CD18 integrins binding to ICAM-1 and ICAM-2 to
neity is unclear; although a correlation with eosinophil activation has nonselectively promote transmigration. VLA-4/VCAM-1 can also exert
been a favored hypothesis, the evidence to support this hypothesis is selective pressure at this stage. In mice, this process is dependent on
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contradictory. 54 the intracellular RAC-binding protein SWAP-70. The activation step
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mediated by chemoattractants expressed on the endothelial surface is
EOSINOPHIL TRAFFICKING AND another potential point of eosinophil selection, as shown by the effect
of exogenously added chemoattractants such as eotaxin, but the identity
TISSUE ACCUMULATION of the endogenous chemoattractant involved and the extent to which it
Eosinophils are not normally found in tissues other than the gut and the is selectively expressed in eosinophilic inflammation remains to be con-
appearance of increased numbers of these cells can be a notable feature clusively resolved. Orosomucoid-like 3 (ORMDL3), a molecule that has
of the pathology of a number of diseases. The normal pattern of gut been identified by genetic epidemiology to be associated with asthma, is
homing of eosinophils is likely to be mediated by CCL-11 (eotaxin 1), expressed by eosinophils and gene deletion in a mouse model resulted
which is constitutively expressed in the gut, and the integrin α β bind- in reduced adhesion and recruitment into the lung. 68
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ing to mucosal addressin cell adhesion molecule (MAdCAM)-1, which Once the eosinophil has transmigrated through the endothelium
is selectively expressed in the intestine. Type 2 innate lymphoid cells it has to migrate through the basement membrane and into the tissue.
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are central to this process, constitutively producing IL-5, which gener- Chemokines as well as other eosinophil chemoattractants are likely to
ates an eosinophilia, and IL-13, which stimulates production of eotaxin. be central to this process (Table 62–3). Many eosinophil-active chemok-
Activation of innate lymphoid cell (ILC)-2 was modulated by nutrient ines bind to the chemokine receptor (CCR)-3 and deletion of this gene
intake and circadian rhythms, which may explain the circadian cycling severely impairs eosinophil migration into the lung in the mouse asthma
of blood eosinophils. Although an eosinophilia can accompany a model. The three specific eosinophil chemokines, eotaxins 1 to 3, appear
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Kaushansky_chapter 62_p0947-0964.indd 950 9/21/15 10:56 AM