Page 1310 - Hematology_ Basic Principles and Practice ( PDFDrive )

1156 Part VII Hematologic Malignancies

4
including IL-3, GM-CSF, and IL-5. The most potent and specific adhesion molecule-1 (VCAM-1 = CD106). Selective recruitment of
eosinophilopoietic growth factor is IL-5. Eosinophils are derived eosinophils is mediated by adhesion to VCAM-1 via the β1 integrin
from multipotent or bipotent colony-forming progenitor cell units very late activation antigen-4 (VLA-4 = CD49d/CD29), which is
(CFUs). Bipotent CFUs giving rise to eosinophils and basophils expressed by eosinophils but not by blood neutrophils.
(CFU-eo/ba) are frequently detected in the BM and PB in healthy Eosinophil migration is regulated by several different chemotactic
8
individuals, as well as in various disease states. By contrast, pro- factors, including various chemokines (SDF-1, eotaxins, IL-8, regu-
genitor cells selectively giving rise to eosinophils and mast cells lated on activation, normal T-cell expressed and secreted [RANTES],
(CFU-eo/mast) are very rare. At an early stage of progenitor cell and others), the complement fragment C5a, platelet-activating factor
development, eosinophil-committed progenitors exhibit CD34 and (PAF), and several eosinotropic cytokines, such as IL-5 or GM-CSF,
CD38, and coexpress receptors for IL-3, GM-CSF, and IL-5. Later, which also prime eosinophils for enhanced migratory responses to
CD34 is diminished, whereas the interleukin receptors continue to be PAF and IL-8. In addition, IL-2, leukotriene B 4, and the lymphocyte
expressed, and several additional, functionally important cell surface chemoattractant factor (LCF = IL-16) can induce eosinophil migra-
antigens are acquired by maturing eosinophils. tion. At least for neoplastic eosinophils, a most potent chemoat-
IL-3, GM-CSF, and IL-5 promote eosinophil differentiation in tractant appears to be SDF-1, a stromal cell-derived chemokine that
10
hematopoietic progenitor cells and eosinophil maturation of lineage- binds to CXCR4 (CD184) on normal and neoplastic eosinophils.
restricted precursors, as well as the recruitment, priming, activation, Other potent chemoattractants for (neoplastic) eosinophils are the
9
and survival of mature eosinophils. Whereas IL-3 and GM-CSF eotaxins (eotaxin-1, -2, -3) that bind to and signal through the
9
also affect other hematopoietic lineages, including basophils, IL-5 chemokine receptor CCR3 (CD193; see Table 71.5). Depending
acts as a more lineage-restricted (eosinophil-targeting) cytokine. on the underlying disease, the cell type(s) involved, and the presence
Therefore, IL-5 and IL-5 receptors have been recognized as major of comorbidities (triggering, e.g., local or systemic inflammation)
targets of therapy in diseases associated with (reactive) HE. The all these chemotactic factors may act together to trigger eosinophil
high-affinity receptor for IL-5 is composed of an IL-5–specific alpha recruitment and accumulation in the affected (often inflamed) tissue
chain (CD125) and a beta chain (CD131) that mediates intracel- sites. Likewise, in several reactive conditions, IL-5 and eotaxin
lular signaling and is shared also by the high-affinity receptors for reportedly cooperate locally to promote eosinophil migration and
GM-CSF (CD116/CD131) and IL-3 (CD123/CD131; see Table tissue HE.
71.5). Expression of high-affinity IL-5 receptors is an important The primary source of eosinophil chemotactic factors often remains
prerequisite for specific cellular responses to “physiologic doses” of unknown. In many disease states accompanied by HE, eosinophil
IL-5. Overexpression of IL-5 is observed in many reactive conditions chemotactic factors may be produced by microenvironmental cells,
and disease states associated with (reactive) HE. Correspondingly, including fibroblasts, endothelial cells, macrophages, and mast cells.
IL-5 transgenic mice develop profound eosinophilia, and IL-5 Several of these chemotaxins, like SDF-1, are produced by stromal
knockout mice do not develop HE in response to allergic stimuli or cells in a paracrine fashion. For example, in neoplastic eosinophils, the
a helminth infection. Under various reactive conditions accompanied F/P mutant triggers expression and release of oncostatin M (OSM),
by HE, IL-5 is produced primarily by activated Th2-type helper cells. which in turn induces fibroblast and endothelial cell proliferation
However, although activated T cells are considered a primary and but also the expression and release of SDF-1 from these cells, thereby
11
most important source of eosinophilopoietic cytokines, like IL-5, augmenting the accumulation of additional eosinophils. In this
other cell types, such as mast cells, macrophages, natural killer (NK) regard, it is noteworthy that the SDF-1 receptor CXCR4 is not only
cells, and stromal cells, also produce these cytokines. In myeloid neo- expressed on mature eosinophils, but also on pluripotent stem cells
plasms with HE, clonal expansion of eosinophils usually is a growth and eosinophil-committed precursor cells. Depending on the type of
factor-independent process. Moreover, depending on the underly- underlying neoplasm, eosinophil chemotactic cytokines may also be
ing disease, neoplastic eosinophils may produce eosinophilopoietic produced in an autocrine manner.
cytokines in an autocrine manner, thereby augmenting tissue and
blood HE.
Role of Mast Cells in Eosinophil Recruitment
and Accumulation
Mobilization and Migration of Eosinophils to
Sites of Inflammation In various inflammatory and allergic reactions, several different inter-
actions between eosinophils and mast cells have been postulated. For
In healthy individuals as well as in reactive states, eosinophils circulate example, mast cells provide the immediate stimuli upon activation
only briefly in the PB, and then transit to extravascular sites. Depend- to initiate allergic inflammation, resulting in eosinophil recruitment
ing on environmental factors and demand, eosinophils localize during the later phases following an allergen encounter. In addition,
preferentially in tissues and organs exposed to external environments, mast cells and eosinophils are often increased in numbers in allergic
principally the submucosal membranes and loose connective tissues reactions, but also in nonallergic inflammatory conditions and even
of the skin, GI tract, genital tract, and lungs. During an acute in neoplastic states. Both cell types express a similar profile of che-
or chronic inflammatory process, larger numbers of eosinophils motactic receptors, such as CCR3, and both respond to eotaxins and
9
may be recruited actively into local tissue sites. The mobilization RANTES (CCL5), leading to their recruitment into local tissue sites.
of eosinophils from the vasculature into (vascularized) tissues is a Mast cells and eosinophils also interact with each other via cell–cell
multistep process that involves their rolling on vascular endothelial contact and through several different soluble mediators. Likewise,
cells and their subsequent adhesion to endothelium via L-selectin, mast cell-derived heparin binds and stabilizes various chemokines,
followed by binding to intercellular adhesion molecule-1 (ICAM-1 including the eotaxins. In addition, mast cells are a source of various
4
= CD54) through a CD18/CD11a/b-dependent mechanism. Expres- cytokines involved in the regulation of eosinophil adhesion, migration,
sion of selectins on endothelial cells is triggered by histamine and and function. As previously mentioned, mast cells express and release
other mediators, whereas expression of ICAM-1 on endothelial cells histamine and TNF-α, and thereby facilitate eosinophil recruitment.
is induced by various proinflammatory cytokines, such as tumor Mast cell proteases appear to have a dual action on eosinophil func-
necrosis factor-α (TNF-α). As both histamine and TNF-α are tions. Mast cell-derived chymase suppresses eosinophil apoptosis
produced and are rapidly provided by (activated) mast cells, these and induces the release of IL-6 and various chemokines (CXCL1,
cells are considered to play a crucial role in eosinophil recruitment CXCL8, CCL2) from eosinophils. Beta-tryptase, on the other hand,
in various allergic and other inflammatory reactions. However, the can cleave eotaxin and RANTES, and thereby may limit eosinophil
recruitment of eosinophils is a complex process involving many chemotaxis. Apart from these interactions, eosinophils and mast cells
different mechanisms and molecules, such as E-selectin, endothelial- may sometimes also derive from the same stem or progenitor cell
leukocyte adhesion molecule 1 (ELAM-1 = CD62E) or vascular cell compartment, and therefore may express the same driver mutant,