The eosinophil is a terminally differentiated, end-stage leukocyte that resides predominantly in submucosal tissue and is recruited to sites of specific immune reactions, including allergic diseases. The mean generation time for eosinophils in the bone marrow is approximately 2-6 days. They mainly settle in the tissue where their number is about one hundred times higher than in the blood. Like other granulocytes, they posses a polymorphous nucleus, although with only two lobes and no nucleolus. The eosinophil cytoplasm contains large ellipsoid granules with an electron-dense crystalline nucleus and partially permeable matrix. In addition to these large primary crystalloid granules, there is another granule type that is smaller and lacks the crystalline nucleus.
These large specific granules are the principal indentifying feature of eosinophils. They contain four distinct cationic proteins which exert a range of biological effects on host cells and microbial targets: major basic protein (MBP), oesinophil cationic protein (ECP), eosinophil derived neurotoxin (EDN), and eosinophil peroxidase (EPO). Basophils contain about one fourth as much MBP as did eosinophils and detectable amounts of EDN, ECP and EPO. Small amounts of EDN and ECP were also found in neutrophils.
These proteins have major effects not only on the potential role of eosinophils in host defence against helminthic parasites, but also in contributing to tissue dysfunction and damage in eosinophil related inflammatory and allergic diseases. As MBP lack enzymatic activity, one mechanism whereby this highly cationic polypeptide may exert its toxic activities is by interactions with lipid membranes leading to their derangement. Both MBP and EPO have been shown to act as selective allosteric inhibitors of agonist binding to M2 muscarinic receptors. Thus, these proteins may contribute to M2 receptor dysfunction and enhance vagally mediated bronchoconstriction in asthma. EDN specifically damage the myelin coat of neurons.
In addition, histaminase and a variety of hydrolytic lysosomal enzymes are also present in the large specific granules.
Among the typical small granule enzymes are aryl sulphatase, acid phosphatase and a 92 kDa metalloproteinase, a gelatinase.
Only recently has it been recognized that eosinophils are
capable of elaborating cytokines which include those with
potential autocrine growth-factor activities for eosinophils and
those with potential roles in acute and chronic inflammatory
responses. Three cytokines have growth-factor activities for
eosinophils: granulocyte-macrophage colony-stimulating factor
(GM-CSF), IL-3 and IL-5. Other cytokines produced by human
eosinophils that may have activities in acute and chronic
inflammatory responses include IL-1
,
IL-6, IL-8, TNF-
and both
transforming growth factors, TGF-
and TGF-
.
Eosinophils also participate in hypersensitivity reactions,
especially through two lipid inflammatory mediators, leukotriene
C
(LTC
) and platelet
activating factor (PAF). Both mediators
contract airway smooth muscle, promote the secretion of mucus,
alter vascular permeability and elicit eosinophil and neutrophil
infiltration. In addition to the direct activities of these
eosinophil-derived mediators, MBP by a non-cytotoxic mechanism can
stimulate the release of histamine from basophils and mast cells,
and EPO from mast cells. Thus, once stimulated, eosinophils can
serve as a local source of specific lipid mediators as well as
induce the release of mediators from mast cells and basophils.
The processes that lead to the accumulation of eosinophils within tissue sites of specific inflammation, as for other leukocytes, involve numerous sequential interactions that enable eosinophils to adhere to and then transmigrate through the endothelium and to respond to local chemoattractants. The adhesion of eosinophils to endothelium include CD18-dependent pathways, interaction between E-selectin and P-selectin and adherence to VCAM by means of very late antigen 4 (VLA-4) expressed on the eosinophil.
The eosinophil granule content is released following similar stimuli to neutrophil granules (e.g. during phagocytosis of opsonized particles and by chemotactic factors). However, whereas the neutrophil lysosomal enzymes act primarily on material engulfed in phagolysosomes, the eosinophil granule content act mainly on extracellular target structure such as parasites and inflammatory mediators.
The eosinophil functional activity, like the immune response
in general, may be beneficial or harmful for the organism.
Compared to neutrophils, eosinophils have limited phagocytic
activity which is mainly aimed at killing multicellular parasites.
Another beneficial activity is the inactivation of mediators of
anaphylaxis. Thus, for example, acylsulphatase B may inactivate
the
slow-reacting substance of anaphylaxis (SRS-A, a mixture
of LTC
, LTD
and LTE
),
phospholipase D destroys the platelet
lytic factor, histaminase degrades histamine and lysophospholipase
(phospholipase B) may inactivate the membrane-active
lysophosphatides.
In addition to the acute release of protein, cytokine and
lipid mediators of inflammation, eosinophils likely contribute to
chronic inflammation, including the development of fibrosis.
Eosinophils are the major source of the fibrosis-promoting
cytokine TGF-
in nodular sclerosing
Hodgkin's disease. Additional
roles for the eosinophil in modulating extracellular matrix
deposition and remodeling are suggested by studies of normal wound
healing. During dermal wound healing eosinophils infiltrate into
the wound sites and sequentially
express TGF-
early, and TGF-
later, during wound healing.