New Light Shed On The Enigmatic Eosinophil Granulocyte; A Versatile Cell Of The Immune System

Abstract

Eosinophils normally constitute only a few per cent of circulating leukocytes, though they are more numerous in tissues vulnerable to attack by environmental microorganisms. Eosinophils can kill invasive parasites, but they also have immunoregulatory functions and may be involved in, for example, the connective tissue remodeling that occurs in conjunction with inflammation. Although their effects may be beneficial to the host, for instance in the event of helminthic infestation, they may also cause tissue damage, for example in allergy and asthma. Recent years have witnessed significant advances in our knowledge of these fascinating but still enigmatic cells. The eosinophil granulocyte was first described in 1879 by Paul Ehrlich, who discovered a blood cell that had high affinity for acid dyes and, in particular, eosin (1) (Figure 1). Eosin, which gives the cells their characteristic red-orange color, is named after Eos, the goddess of dawn in Greek mythology. Paul Ehrlich also put forward the hypothesis that eosinophils develop in the bone marrow (2) and exert their functions in the peripheral tissues. All vertebrates seem to have eosinophils in their blood, but these cells have also been described in more primitive organisms such as sharks, turtles and snakes (3). However. there are differences in morphology, and a comparison of eosinophils from different species also reveals considerable differences in the protein content of their characteristic cytoplasmic granules. For example, in contrast to many vertebrates, eosinophils from the cat, rhino, hyena and okapi lack peroxidase (3).

Figure 1.

Eosinophils in blood from a patient with the idiopathic hypereosinophilic syndrome. The picture was obtained using light microscopy and May-Grunwald-Giemsa staining on a smear from peripheral blood.

Figure 2a.

Electron micrograph of an eosinophil granulocyte. The cell has a typical bibbed nucleus (n). In the cytoplasm the characteristic specific granules are seen (arrows). containing crystalloid core.

Figure 2b.

Schematic drawing of the different compartments in the specific granules. Major basic protein (MBP) constitutes the crystalloid core while eosinophil cationic protein (ECP), eosinophilderived neurotoxin (EDN), eosinophil peroxidase (EPO) and cytokines are stored in the matrix of granules.

Figure 2c.

Electron micrograph showing a Charcot-Leyden crystal with a typical hexagonal shape. The ultra thin section was incubated with antibody against CLC protein. The antibody was visualised with protein A-colloidal gold and appears as small black dots scattered over the surface of the crystalloid structure, indicating the presence of CLC protein

Figure 3.

Comparison of type 1 (Thl) and type 2 (Th2) cytokines. Type I cytokines mainly transmit cell-mediated immunity whereas type 2 cytokines transmit humoral immunity. The two systems balance each other by crosswise inhibition, mediated by IFNy IL-12 and IL-4 IL-10, respectively (artist: Piroska von Gegerfeldt).

Figure 4.

Schematic drawing of eosinophil recruitment to the site of an inflammatory reaction.

1. Tissue cells, e.g. lymphocytes (Ly) or macrophages (Mø), stimulate endothelial cells in postcapillary venules to express surface adhesion molecules on their surface.

2. Initially the cell is ”marginated” in the blood vessel and starts ”rolling” along the endothelium, a process mediated by adhesion molecules of the selectin type.

3. The eosinophil granulocytes are activated, in particular by inflammatory mediators released by the endothelial cells, and subsequently bind strongly to the endothelial cells. This firm binding is mediated through ß1- and ß2-integrins. The activation of ß2-integrins also cause a shape change and the eosinophil becomes flattened.

4. Several inflammatory mediators produced at the site of inflammation stimulate the eosinophil granulocytes to leave the blood vessel, using its ß1- and ß2-integrins, and enter the tissue where it exerts its function.

(artist: Piroska von Gegerfeldt)

Figure 5.

Two main principles for eosinophils to release their granule proteins (degranulation):

1. The cell phagocytoses bacteria with immunoglobulins and complement molecules on their surface. The bacteria are enclosed in an invagination of cell membrane that ñnally becomes a phagosome of their cytoplasm. Specific granules are transported to the phagosome (1), and after fusion (2) the granular content is released (3) and the cytotoxic process started.

2. The eosinophil granulocyte attacks a parasite too big to phagocytose, resulting in ”frustrated” phagocytosis. The granules are transported to the part of the cell membrane that is in contact with the parasite (1). The membranes of the granule and the eosinophil plasma membrane fuse (2) followed by release of the granule content onto the surface of the parasite (3) where the cytotoxic effects are exerted. (artist: Piroska von Gegerfeldt)