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EOSINOPHIL

Eosinophils are leukocyte (white cells) found in the blood and connective tissues of all vertebrates studied so far. P Ehrlich described eosinophils in 1879, although they were probably observed much earlier. Their major functions are defense against helminth parasites, allergic responses, tissue inflammation and immunity. However, is increasingly knowledge their role in the homeostasis of tissues under remodeling processes, both healthy and damaged tissues. Eosinophils are a member of granulocytes (a group of leukocytes), together with basophils and neutrophils because their cytoplasm contains many granules. The eosinophil is because of the strong affinity for the dye eosin, which stain in pink-red the acid molecules included in these granules. In healthy conditions, eosinophils are about 2 % to 4 % of the total leukocytes of the blood. Eosinophil can exit the blood stream and move to the connective tissues of the body organs, where their proportion in the total leukocytes is quite higher. Curiously, eosinophils have been found in a wide variety of animals like crustacean, insects, mammals, fish, and birds, suggesting that the functions they perform have been conserved during evolution.

1. Morphology

Eosinophils are rounded cells of about 15 µm in diameter, larger than other blood cells like erythrocytes, lymphocytes and basophils. At light microscopy, eosinophils show a nucleus with two lobes, with a thin nuclear bridge connecting both lobes (Figure 1). The morphology of the nucleus may vary depending on the species. For example, it shows a ring-like morphology in rats. The cytoplasm contains many granules, known as specific granules, which are stained in orange-red with acidic dyes like eosin.

Eosinophil
Figure 1. Eosinphils. A monocyte is also observed in the image on the left. In the fourth image, a lymphocyte can be also observed.

At transmission electron microscopy, the specific granules of eosinophils show a crystallized central structure arranged in parallel layers, surrounded by a more or less electron-dense matrix (Figure 2). This structure is patent in rodent and human eosinophils. Furthermore, there is a number of azurophilic granules in the cytoplasm, referred as non-specific granules. They are actually lysosomes containing acid hydrolases and other hydrolytic enzymes that contribute to eosinophil functions. In the cytoplasm, there are lipid bodies and tubulo-vesicular structures known as EoSV ( eosinophil sombrero vesicles).

Eosinophil
Figure 2. Transmission electron microscopy image showing specific granules of an eosinphil.

2. Origin and distribution

Eosinophils are originated in the bone marrow, where a precursor cell of the granulocyte lineage, after 8 days of maturation, becomes an eosinophil (Figure 3). However, by using specific cell markers, eosinophil precursors have been found in the blood stream and in the connective tissues, meaning that not all eosinophil precursors finish their differentiation in the bone marrow. Eosinophils use the blood stream as a way to reach the final destination and perform their function. They remain in the blood for about 10 hours and then cross the endothelium of the blood vessels to get to the connective tissues, where they can live for another one or two weeks (Figure 4). They are more abundant in the connective tissue of the lamina propria of the intestine and stomach. Groups or a higher number of eosinophils can be found in other tissues after infections. Eosinophils are able to invade tissues attracted by specific signals released during normal development, tissue repairing or chronic diseases. The features of circulating eosinophils are different from those found in connective tissues. For example, they can express specific cell markers depending on the tissue they are found and sometimes can be morphologically distinguished.

Eosinphil
Figure 3. Cell lineages of blood cell types. Progenitors cells are found in the bone marrow and macrophages in the connective tissues.
Eosinófilo en mucosa
Figure 4. Eosinophils showing pinky-redish cytoplasm and ring-like nucleus in the mucosa of the stomach of a mouse.

The usual number of eosinophis in tissues is low. However, they become more abundant in healthy tissues with high renewing rate or with high proliferation activity of adult stem cells (small intestine, endometrial layer delimiting the uterus, bone marrow and timus), tissues undergoing morphogenesis and development (mammary glands), in the regions where Peyer plates are formed, in lungs during the postnatal development, and in the beige fat formation regions. They are also abundant during the normal tissue repairing after damages, in those tissues with intense remodeling like after infection by helmints, in lungs with acute damage, fibrosis, cancer, allergic diseases in the intestine, skin and aerial pathways, and in the endocrinopathies.

3. Functions

Unlike other leukocytes, the functions of eosinophils are quite variable and somehow non precise (Figure 5). Actually, they don't look like to be necessary for the animal since the lack of eosinophils does not have a lethal effect. Traditionally, they have been involved in the defense against helminth infection since eosinophyls can recognize these parasites and release toxic substances to kill them. Nowadays, it is known that eosinophyls have a much wider variety of functions and they are thought to be involved in allergies, inflammatory reactions, immune responses, and other homeostatic roles in many parts of the body, particularly in the respiratory airways. It is also observed an increase of eosinophils during asthmatic processes, probably induced by the inflammation produced during this illness. In this case, eosinophils may be the cause of asthma to get worse.

Eosinpphil
Figure 5. Main functions of eosinophils (adapted from Rothenberg and Hogan, 2006).

It is clear that eosinophils are not only found in those tissues undergoing infection or inflammation, but they are common among the cells present in healthy tissues. However, these healthy tissues with eosinophils are under morphogenetic processes, regeneration, high activity of adult stem cells, or under changes in the metabolic rate. Thus, it is thought that eosinophils are performing the same function in damaged and healthy tissues: helping recover tissular homeostasis.

The number of oeosinophils in the blood stream is indicative of an infection process. Normally, the number of eosinophils produced in the bone marrow is low, and therefore there is a low number of circulating eosinophils. In healthy humans, eosinophils are concentrated in the intestine mucosa maintaining the connective tissue homeostasis and controlling the intestinal bacteria. The number of eosinophils increase in the blood stream (more than 700 eosinophils/ml) during helminth infections, during many allergic reactions (like bronchial asthma, eczema, and allergies by drugs) and other diseases. It may also happen that the number is increased in some tissues, but not so much in the blood, as in the severe bronchial asthma with eosinophils in the sputum.

The eosionophil functions depend on the composition of the granular content. The granules are known as crystalloid granules because they show a crystallized core. They content four main proteins: the mayor basic protein (MBP) provides acidophilia and is located in the crystal structure, the eosinophilic cationic protein (ECP), the eosinophil peroxidase (EPO) and the eosinophil derived neurotoxin (EDN). They are no exclusiveof eosinophils since MBP and EPO are found in basophils, and EDN and ECP are found in neutrophils. These and other molecules stored in the granules make possible a very fast response (less than one hour).

All mollecules mentioned above have activity against parasites because they are cytotoxic and contribute to the destruction of pathogens. For example, eosinophils are able to get attached to other cells and kill them thanks to their cationic proteins that form pores in the membrane of the pathogen cell. These pores are the entry way to other molecules that definitely kill the cell. However, these proteins have other non-toxic functions since they are involved in adaptive and innate immunity by interactions with T lymphocytes and mastocytes.

Specific granules contain enzymes like histaminases and arylsulphatase, which are involved in inflammation after allergy processes. They contribute to neutralize the effects of histamine released by mastocytes and leukotrienes released by basophils.

Eosinophil activation is initiated by combined effect the cytokines released by antigen presenting cells, mastocytes, and T and B lymphocytes. Three mechanisms have been proposed to explain the release of eosinophil granule content. 1. Exocytosis, when eosinophils meet a large target like helminth parasites. 2. Piecemeal degranulation (PMD), when granule content is moved into the EoSV bodies, which are formed in the granule membrane and fused with the plasma membrane. The formation of EoSV bodies is stimulated along with the eosinophil activation. The membrane demand is met with tubular structures found in the granules. 3. Degranulation, which is associated with the eosinophil lysis. It appears to be the most common mechanism and would explain why there are so many eosinophil granules in the tissues affected by an inflammatory reaction caused by helminth parasites or allergic reactions.

Eosinophils may perform several immune roles such as presenting antigens and favor the inflammatory response. The influence in the inflammatory response is through a wide variety of cytokines, which are able to promote T lymphocyte proliferation and mastocyte activity. Eosinophils may release more than 35 different cytokines, chemokines and growth factors. At least 10 of these molecules are stored in the granules as preformed molecules, mainly around the crystalloid. Other molecules, however, are stored in small vesicles. The ability of eosinophils to synthesize and release a large variety of active molecules means that they are involved in many functions.

Other functions performed by eosinophils are related with the normal functioning of some organs. For example, there are waves of eosinophils correlating with the hormones cycles, which are thought to be related with a reproductive activity. They are also abundant in mammary glands during the postnatal period, and they may help with the normal development of these glands. In the thymus, there are also perinatal waves of eosinophils that appear to be important for eliminating apoptotic thymocytes.

Bibliografía

Davoine F, Lacy P. 2014. Eosinophil cytokines, chemokines, and growth factors: emerging roles in immunity. Frontiers in immunology 10. doi:10.3389/fimmu.2014.00570.

Muniz VS, Weller PF, Neves JS. 2012. Eosinophil crystalloid granules: structure, function, and beyond. J Leukoc Biol. 92:281-288.

Padigel UM, Nolan TJ, Schad GA, Abraham D. 2006. Eosinophils can function as antigen-presenting cells to induce primary and secondary immune responses to Strongyloides stercoralis. Infection and immunity. 74(6): 3232–3238.

Rothenberg ME, Hogan SP. 2006. The eosinophil. Annual review of immunology. 6. 24:147-174.

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