Eosinophil

Function

Following activation, eosinophils effector functions include production of the following:

• Cationic granule proteins and their release by degranulation
• Reactive oxygen species such as hypobromite, superoxide, and peroxide (hypobromous acid, which is preferentially produced by eosinophil peroxidase)
• Lipid mediators like the eicosanoids from the leukotriene (e.g., LTC₄, LTD₄, LTE₄) and prostaglandin (e.g., PGE₂) families
• Enzymes, such as elastase
• Growth factors such as TGF beta, VEGF, and PDGF
• Cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-13, and TNF alpha

There are also eosinophils that play a role in fighting viral infections, which is evident from the abundance of RNases they contain within their granules, and in fibrin removal during inflammation. Eosinophils, along with basophils and mast cells, are important mediators of allergic responses and asthma pathogenesis and are associated with disease severity. They also fight helminth (worm) colonization and may be slightly elevated in the presence of certain parasites. Eosinophils are also involved in many other biological processes, including postpubertal mammary gland development, oestrus cycling, allograft rejection and neoplasia. They have also been implicated in antigen presentation to T cells.

Eosinophils are responsible for tissue damage and inflammation in many diseases, including asthma. High levels of interleukin-5 has been observed to up regulate the expression of adhesion molecules, which then facilitate the adhesion of eosinophils to endothelial cells, thereby causing inflammation and tissue damage.

An accumulation of eosinophils in the nasal mucosa is considered a major diagnostic criterion for allergic rhinitis (nasal allergies).

Granule proteins

Following activation by an immune stimulus, eosinophils degranulate to release an array of cytotoxic granule cationic proteins that are capable of inducing tissue damage and dysfunction. These include:

• major basic protein (MBP)
• eosinophil cationic protein (ECP)
• eosinophil peroxidase (EPX)
• eosinophil-derived neurotoxin (EDN)

Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues. Eosinophil cationic protein and eosinophil-derived neurotoxin are ribonucleases with antiviral activity. Major basic protein induces mast cell and basophil degranulation, and is implicated in peripheral nerve remodelling. Eosinophil cationic protein creates toxic pores in the membranes of target cells, allowing potential entry of other cytotoxic molecules to the cell, can inhibit proliferation of T cells, suppress antibody production by B cells, induce degranulation by mast cells, and stimulate fibroblast cells to secrete mucus and glycosaminoglycans. Eosinophil peroxidase forms reactive oxygen species and reactive nitrogen intermediates that promote oxidative stress in the target, causing cell death by apoptosis and necrosis.

Clinical significance

Blood count

Strong evidence indicates that blood eosinophil counts can predict the effectiveness of specific anti-inflammatory drugs. Despite their increasing use in clinical practice, data on "normal" blood eosinophil counts remain insufficient. Due to the right-skewed distribution of these counts, median values are more informative than mean values for determining normal levels. Few large-scale studies have reported median blood eosinophil counts, with the median for healthy individuals being 100 cells/μL and the 95th percentile at 420 cells/μL. Thus, it is now evident that the normal median blood eosinophil count in healthy adults is around 100 cells/μL, with counts above 400 cells/μL considered outside the normal range. Current cutoffs such as 150 or 300 cells/μL used in asthma or COPD management fall within the normal range.

Eosinophilia

An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microliter of blood is called an eosinophilia, and is typically seen in people with a parasitic infestation of the intestines; autoimmune and collagen vascular disease (such as rheumatoid arthritis) and Systemic lupus erythematosus; malignant diseases such as eosinophilic leukemia, clonal hypereosinophilia, and Hodgkin lymphoma; lymphocyte-variant hypereosinophilia; extensive skin diseases (such as exfoliative dermatitis); Addison's disease and other causes of low corticosteroid production (corticosteroids suppress blood eosinophil levels); reflux esophagitis (in which eosinophils will be found in the squamous epithelium of the esophagus) and eosinophilic esophagitis; and with the use of certain drugs such as penicillin. But, perhaps the most common cause for eosinophilia is an allergic condition such as asthma. In 1989, contaminated L-tryptophan supplements caused a deadly form of eosinophilia known as eosinophilia-myalgia syndrome, which was reminiscent of the toxic oil syndrome in Spain in 1981.

Eosinophils play an important role in asthma as the number of accumulated eosinophils corresponds to the severity of asthmatic reaction. Eosinophilia in mice models are shown to be associated with high interleukin-5 levels. Furthermore, mucosal bronchial biopsies conducted on patients with diseases such as asthma have been found to have higher levels of interleukin-5 leading to higher levels of eosinophils. The infiltration of eosinophils at these high concentrations causes an inflammatory reaction. This ultimately leads to airway remodelling and difficulty of breathing.

Eosinophils can also cause tissue damage in the lungs of asthmatic patients. High concentrations of eosinophil major basic protein and eosinophil-derived neurotoxin that approach cytotoxic levels are observed at degranulation sites in the lungs as well as in the asthmatic sputum.

Treatment

Treatments used to combat autoimmune diseases and conditions caused by eosinophils include:

• corticosteroids – promote apoptosis. Numbers of eosinophils in blood are rapidly reduced
• monoclonal antibody therapy – e.g., mepolizumab or reslizumab against IL-5, prevents eosinophilopoiesis, or benralizumab against IL-5 receptor, which eliminates eosinophils through ADCC
• antagonists of leukotriene synthesis or receptors
• imatinib (STI571) – inhibits PDGF-BB in hypereosinophilic leukemia

Monoclonal antibodies such as dupilumab and lebrikizumab target IL-13 and its receptor, which reduces eosinophilic inflammation in patients with asthma due to lowering the number of adhesion molecules present for eosinophils to bind to, thereby decreasing inflammation. Mepolizumab and benralizumab are other treatment options that target the alpha subunit of the IL-5 receptor, thereby inhibiting its function and reducing the number of developing eosinophils as well as the number of eosinophils leading to inflammation through antibody-dependent cell-mediated cytotoxicity and eosinophilic apoptosis. Lysosomotropic agents are an efficient means to target the lysosome-like eosinophil granules inducing eosinophil apoptosis.

Animal studies

Within the fat (adipose) tissue of CCR2 deficient mice, there is an increased number of eosinophils, greater alternative macrophage activation, and a propensity towards type 2 cytokine expression. Furthermore, this effect was exaggerated when the mice became obese from a high fat diet.

Mouse models of eosinophilia from mice infected with T. canis showed an increase in IL-5 mRNA in mice spleen.

Mouse models of asthma from OVA show a higher TH2 response. When mice are administered IL-12 to induce the TH1 response, the TH2 response becomes suppressed, showing that mice without TH2 cytokines are significantly less likely to express asthma symptoms.