What are eosinophils and what are they for

A type of white blood cell involved mainly in parasitic infections and allergic reactions.

The population of white blood cells (or leukocytes) includes various types of cells, endowed with different immune functions. Eosinophils are among them.

Poorly represented in circulating blood, where they normally constitute 1 to 6% of the total white blood cells, eosinophils are mainly present in other districts of the body, in particular in those that are in direct contact with the external environment such as the skin, respiratory tract, digestive tract and genital tract.

Their primary role within the immune system is connected on the one hand to the defense reactions against certain infectious diseases (caused by viruses and bacteria) and certain parasitic infections, and on the other to the onset of allergic manifestations (the so-called hypersensitivity reactions). But their competences – still not fully defined by the world of science – seem to be much more articulated.

From bone marrow to connective tissue

Eosinophils belong, together with neutrophils (which are the most numerous among white blood cells) and basophils (the least numerous), to the group of granulocytes. These cells are so called because they have granulations in their cytoplasm, which can be made visible under the light microscope with particular dyes used in histology, especially eosin Y and eosin B.

The granules of the different types of cells absorb different dyes with greater or lesser affinity: it is precisely from their specific dye, eosin, that eosinophilic granulocytes take their name.

The cytoplasmic granules of eosinophils contain a number of active chemical compounds, which are selectively released outside in situations where eosinophils perform their function as immune cells. These are:

• numerous enzymes, including lysosomal hydrolases, peroxidases, aryl-sulfatase, phospholipases, histanases;
• some specific protein molecules, such as major basic protein (MBP), eosinophilic cationic protein (ECP), eosinophil-derived neurotoxin (EDN).

Depending on their mechanism of action, these compounds exert:

• a harmful effect on parasitic organisms;
• a protective function against harmful substances released during parasitic infections;
• a modulating action with respect to the release of proinflammatory molecules by other cells of the immune system (for example histamine, leukotrienes or platelet activating factor that are produced by basophilic granulocytes)
• a regulatory action of the physiological processes of other cell types.

Like all blood cells, eosinophils are produced by the bone marrow, where hematopoietic stem cells develop from the same undifferentiated progenitor cells, which also give rise to red blood cells (also called erythrocytes), other white blood cells and platelets.

In the bone marrow, eosinophils normally mature within 5-6 days, after which they migrate into the blood where they remain in circulation for a few hours, and then go to localize in the tissues in which they perform their functions and where they complete their life cycle in about 8-15 days.

In reality, the duration of the different phases of the life of these cells can be very variable depending on the need for their intervention in the different districts of the body and the level of activation to which they are subjected after their release into circulation.

Moreover, if under normal conditions there is a balance between bone marrow production, release, permanence in peripheral blood and migration into the tissues of eosinophils, in situations of activation of the immune response, in which eosinophils are involved (for example in the course of parasitosis or acute allergic reactions), an acceleration of their discharge from the bone marrow may occur, a redistribution of mature eosinophils between the blood and tissue compartments, a prolongation of their survival.

Usually in the blood there are about 100-500 eosinophils per microliter (μL) or per cubic millimeter (mm3), while the total number of those present in the tissues can be from 100 to 500 times higher than that of circulating eosinophils.

In the recipient organs – as already mentioned those exposed to external agents – eosinophils are located at the level of the connective tissue, that is to say in the layer below the epidermis (the dermis) and in the layer below the superficial mucous membranes of the respiratory system, the gastrointestinal tract and the genital tract.

Multi-tasking cells

The activity of eosinophils is an integral part of those processes of the immune response that are activated by a particular type of lymphocytes that mature in the thymus, the T Helper 2 (TH2).

The main actions of TH2 lymphocytes consist in promoting the production by B lymphocytes of immunoglobulins E (IgE), i.e. antibodies specialized in defense against parasites, reactions to allergens, and secreting interleukins (inflammatory mediators belonging to the cytokine category).

IgE and interleukins induce eosinophils and other immune cells (mast cells and basophilic granulocytes) to release molecules contained in their granules into the extracellular environment. Eosinophils also secrete numerous cytokines and proinflammatory lipid molecules.

Within the complex and intricate network of the immune response, eosinophils themselves play multiple roles:

• intervene in inflammatory reactions, especially if allergic;
• counteract parasitic infections, especially against large parasites such as helminths (worms);
• They exert control over the functions of other cells, immune and otherwise.

The most recent studies have dedicated themselves to clarifying the details of their last prerogative, which are gradually highlighting the functionality of these cells, i.e. the complex role they play within the immune system both in physiological conditions and in the course of diseases.

For example, eosinophils seem to be involved in a relevant way in tissue remodelling: some of the cytokines they release, in fact, have the ability to activate in macrophages the production of enzymes that stimulate the synthesis of collagen, the main protein of connective tissue, and growth factors that induce the proliferation of fibroblasts (the typical cells of connective tissue) and the neoformation of blood vessels.

In addition, some data suggest that under normal conditions eosinophils intervene in metabolic events that occur in adipose tissue and that have to do, among other things, with the regulation of blood pressure and glucose balance. Eosinophils could therefore be implicated in controlling the complications of obesity, hypertension and diabetes.

Finally, they seem to interfere with the replication of cancer cells.

An accentuated production of eosinophils, as occurs physiologically in the course of parasitosis or allergies, determines an increase in their concentration in the blood compared to normal values. This condition, called eosinophilia, can be associated with other pathological conditions and can also occur without apparent cause (in this case we speak of idiopathic or constitutional eosinophilia).

If the increase in eosinophils in the blood in itself does not cause symptoms, their accumulation in the tissues is instead manifested with possibly serious outcomes, related to the dysfunctions of the organs involved.

On the other hand, there may also be a reduction in circulating eosinophils, called eosinopenia, a condition often related to Cushing’s syndrome and bloodstream infections (sepsis), but substantially linked to a state of immunosuppression and which can take place during pharmacological therapies (with corticosteroids, antitumors, interferon, antihistamines), or radiotherapy. Or, this reduction can occur in conjunction with severe systemic bacterial infections, immunodeficiency syndromes, bone marrow diseases, stress. In general, however, eosinophil deficiency does not generate particular problems, because it is adequately compensated by other parts of the immune system. To treat it, it is sufficient to act on its cause.

Secondary eosinophilia: parasitosis, allergy or other?

The abnormalities in the number of circulating eosinophils are detected with the most commonly done hematological analysis, when performing the classic “routine tests“: the blood count (or blood count) associated with leukocyte formula, a laboratory test that allows to know, through the collection of a blood sample, the number of each of the cells circulating in the blood (including, therefore, red blood cells and platelets).

In the leukocyte formula, for each population of leukocytes (neutrophil granulocytes, basophilic granulocytes, eosinophilic granulocytes, lymphocytes, monocytes) absolute values are reported, expressed as the number of cells present in a microliter (μL) or in a cubic millimeter (mm3) of blood, and the percentage values, indicating the share of each cell type in the total white blood cells.

As far as eosinophils are concerned, their concentration in the blood, normally low, can undergo modest alterations even in physiological conditions. In principle, a count of less than 50 cells/μL (or mm3) suggests eosinopenia, a count greater than 500 cells/μL (or mm3) is a sign of eosinophilia and a count of 1,500 cells/μL (or mm3) is considered the threshold beyond which the increase in eosinophils can cause severe tissue damage over time (hypereosinophilia).

A condition of eosinophilia is found in infections by multicellular parasites (protozoa, and especially helminths): in these cases the increase in circulating eosinophils is proportionate to the degree of diffusion of the parasites themselves in the tissues, and therefore to their stage of development. Parasitosis with tissue invasion is common in many tropical countries, while in Western countries helminthiasis are more frequent and remain confined to the intestinal tract, in which eosinophilia may be modest or absent. Among the latter, the most common in Italy are those due to pinworms, helminths belonging to the class of Nematodes, transmitted mainly through the ingestion of their eggs. Toxoplasmosis (an infection caused by a protozoan transmitted from animals to humans) also induces the activation of specific response mechanisms of the immune system that lead to an increase in eosinophils.

Much more rarely a rise in eosinophils is observed in other infectious diseases (Chlamydia pneumonia, cat scratch disease, mononucleosis, scarlet fever, tuberculosis, aspergillosis, etc.).

Eosinophilia, on the other hand, is typical of allergic diseases of various origins (from inhaled allergens, taken with the diet, drugs, etc.): it is particularly marked in atopic forms such as bronchial asthma, in cutaneous forms such as urticaria and atopic dermatitis (commonly called eczema) and in drug allergy, while it can be modest or completely lacking in rhinitis allergic (as in the so-called hay fever) and gastrointestinal allergic reactions.

Eosinophilia of varying degrees can be associated with numerous pathological conditions of different nature. It is often found in adrenal insufficiency, in inflammatory diseases affecting various organs, in case of immunological disorders and also in the presence of tumors. Let’s see some examples.

Rheumatic diseases	Rheumatoid arthritis, scleroderma, systemic lupus erythematosus
Inflammatory pathologies of the digestive tract	Gastroesophageal reflux disease or regurgitation, ulcerative colitis, Chron’s disease, celiac disease
Inflammatory liver diseases	Cirrhosis, cholangitis
Inflammatory lung diseases	Loffler syndrome, eosinophilic pneumonia
Inflammatory cardiac diseases	Dressler syndrome
Inflammatory skin diseases	Pemphigus, psoriasis
Immunological disorders	Immunodeficiency syndromes, graft-versus-host disease
Solid tumors	Carcinoma, melanoma
Blood cancers	Hodgkin’s lymphoma, myeloid leukemia

The differential diagnosis of secondary eosinophilia can therefore involve all medical specialties, from allergology to oncology. In fact, it is up to the specialist interviewed to investigate the condition that caused the increase in eosinophils compared to the reference values, evaluating the patient’s medical history (through questions related to allergies, travel, use of drugs and food supplements and any systemic symptoms) and carrying out both laboratory tests (parasitological and culture tests) and specific tests with the help of diagnostic tools.

Idiopathic forms

According to the classification system currently in use, when a condition of eosinophilia develops in the absence of parasitic, allergic, immunological or other diseases known to be associated, it is called idiopathic forms, or of unknown origin.

Quite widespread in the population is a form called “constitutional eosinophilia” that occurs sporadically or with familial recurrence: it is a non-pathological condition, characterized by a modest increase in circulating eosinophils, which, however, on cytological examination do not show signs of activation.

Much rarer, but possibly serious, is instead the so-called “idiopathic hypereosinophilic syndrome”, a condition characterized by an increase in blood eosinophils greater than 1,500 / μL (or mm3) and long lasting (over 6 months) and multiple organ damage, determined by inflammatory phenomena triggered by eosinophils and other immune cells migrated into the tissues. Although any organ can be involved, the most frequently affected are the lung, heart, spleen, skin and nervous system.

The syndrome can occur in different variants, characterized by genetic abnormalities, serological and cytological characteristics and different clinical manifestations, which can be differentiated on the basis of specific investigations:

• dosage of eosinophils in the blood,
• blood chemistry tests,
• instrumental examinations for the identification of organ damage,
• tissue biopsy,
• medullary needle aspiration.

Some of the patients with hypereosinophilic syndrome may develop serious organ dysfunction, including cardiac dysfunction, mainly caused by a condition of fibrosis of the walls of the heart.

How eosinophilia is treated

In secondary eosinophilia the therapeutic goal must be, of course, to cure the underlying pathology.

When eosinophilia results from a severe idiopathic form or when in a secondary form the lowering of very high blood values, potentially predisposing to organ damage, is not obtained, it is advisable to start treatment with corticosteroids.

If this therapy does not give the desired results, drugs that interfere with cell replication, especially in myeloproliferative diseases, or biological drugs that counteract the action of cytokines may be used.