Eosinophil granulocytes, usually called eosinophils or eosinophiles (or, less commonly, acidophils), are white blood cells that

are one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with allergy and asthma. They are granulocytes that develop during haematopoiesis in the bone marrow before migrating into blood. These cells are eosinophilic or 'acid-loving' as shown by their affinity to coal and tar dyes: Normally transparent, it is this affinity that causes them to appear brick-red after staining with eosin, a red dye, using the Romanowsky method. The staining is concentrated in small granules within the cellular cytoplasm, which contain many chemical mediators, such as histamines and proteinssuch as eosinophil peroxidase, ribonuclease (RNase), deoxyribonucleases, lipase, plasminogen, and major basic protein. These mediators are released by a process called degranulationfollowing activation of the eosinophil, and are toxic to both parasite and host tissues. In normal individuals, eosinophils make up about 1-6% of white blood cells, and are about 1217 micrometers in size.[1] They are found in the medulla and the junction between the cortex and medulla of the thymus, and, in the lower gastrointestinal tract, ovary, uterus, spleen, and lymph nodes, but not in the lung, skin, esophagus, or some other internal organs[vague] under normal conditions. The presence of eosinophils in these latter organs is associated with disease. Eosinophils persist in the circulation for 812 hours, and can survive in tissue for an additional 812 days in the absence of stimulation.[2] Pioneering work in the 1980s elucidated that eosinophils were unique granulocytes, having the capacity to survive for extended periods of time after their maturation as demonstrated by ex-vivo culture experiments. Eosinophil development, migration and activation Eosinophils develop and mature in bone marrow. They differentiate from myeloid precursor cells in response to the cytokines interleukin 3 (IL-3), interleukin 5 (IL-5), and granulocyte macrophage colony-stimulating factor (GM-CSF).[3][4][5]Eosinophils produce and store many secondary granule proteins prior to their exit from the bone marrow. After maturation, eosinophils circulate in blood and migrate to inflammatory sites in tissues, or to sites of helminth infection in response to chemokines like CCL11 (eotaxin-1), CCL24 (eotaxin-2), CCL5 (RANTES), and certain leukotrienes like leukotriene B4 (LTB4) and MCP1/4. At these infectious sites, eosinophils are activated by Type 2 cytokines released from a specific subset of helper T cells (Th2); IL-5, GM-CSF, and IL-3 are important for eosinophil activation as well

as maturation. There is evidence to suggest that eosinophil granule protein expression is regulated by the non-coding RNA EGOT (gene)[6] [edit]Functions of eosinophils Following activation, eosinophils effector functions include production of:
 

cationic granule proteins and their release by degranulation.[7][8][9] reactive oxygen species such as superoxide, peroxide, and hypobromite (hypobromous acid, which is preferentially produced by eosinophil peroxidase).[10] lipid mediators like the eicosanoids from the leukotriene (e.g., LTC4, LTD4, LTE4) and prostaglandin (e.g., PGE2) families.[11] enzymes, such as elastase. growth factors such as TGF beta, VEGF, and PDGF.[12][13] cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, and TNF alpha.[14][8]

 

In addition, eosinophils 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.[14] They have also recently been implicated in antigen presentation to T cells.[15] [edit]Eosinophil 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.[16] These include:
   

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

Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues.[14] Eosinophil cationic protein and eosinophil-derived neurotoxin are ribonucleases with antiviral activity.[17] Major basic protein induces mast cell and basophil degranulation, and is implicated in peripheral nerve remodelling.[18][19] Eosinophil cationic protein creates toxic pores in the membranes of target cells allowing potential entry of

other cytotoxic molecules to the cell,[20]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 glycosaminoglycan.[21] Eosinophil peroxidase forms reactive oxygen speciesand reactive nitrogen intermediates that promote oxidative stress in the target, causing cell death by apoptosis and necrosis.[14] [edit]Eosinophilia Main article: Eosinophilia An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microlitre of blood is called an eosinophilia, and is typically seen in people with a parasitic infestation of the intestines, a collagen vascular disease (such asrheumatoid arthritis), malignant diseases such as Hodgkin's disease, extensive skin diseases (such as exfoliative dermatitis), Addison's disease, in the squamous epithelium of the esophagus in the case of reflux esophagitis, eosinophilic esophagitis, and with the use of certain drugs such as penicillin. In 1989, contaminated Ltryptophan supplements caused a deadly form of eosinophilia known as eosinophilia-myalgia syndrome, which was reminiscent of the Toxic Oil Syndrome in Spain in 1981.

Reference ranges for blood tests of white blood cells, comparing eosinophil granulocyte amount (shown in light red) with other cells. [edit]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., mepoluzimab or reslizumab against IL-5, prevents eosinophilopoiesis antagonists of leukotriene synthesis or receptors

 Gleevec (STI571)- inhibits PDGF-BB in hypereosinophilic leukemia [edit

Abstract: Antihistamines are a common therapy for allergic symptoms. Eosinophilic infiltration is considered a hallmark of allergic inflammation. Eosinophils are capable of mediating airway mucosal damage by producing various inflammatory mediators including cytokines, chemokines, basic granule proteins, lipid mediators, and growth factors. Reduced eosinophil apoptosis is thought to be an important feature in the formation of eosinophilia in allergic diseases such as allergic rhinitis, atopic eczema, and asthma. The aim of this study was to investigate the effects of levocetirizine on the production of inflammatory mediators by eosinophils and on eosinophil apoptosis. The production of cytokines and other inflammatory mediators by human eosinophils was measured by a cytokine antibody array. Apoptosis of isolated human eosinophils was assessed by measuring the relative DNA content of propidium iodide-stained cells. Of the 40 cytokines studied, levocetirizine (1 M) was found to enhance the release of tissue inhibitor of metalloproteinases 1 and 4, matrix metalloproteinase 9, and heparin-binding epidermal growth factor and to attenuate the production of interleukins (IL)-1 and IL-7 and stem cell factor in lipopolysaccharide-stimulated human eosinophils. Levocetirizine did not alter constitutive eosinophil apoptosis or eosinophil survival induced by IL-5, granulocyte/macrophage colonystimulating factor, tumor necrosis factor , or salbutamol. The results of this study suggest that levocetirizine modulates the profile of inflammatory mediators including cytokines, growth factors, proteinases, and antiproteinases produced by eosinophils, which may be of importance in allergic inflammation and airway remodeling. However, eosinophil longevity seems not to be modulated by levocetirizine. Keywords: Airway remodeling; allergic inflammation; allergic rhinitis; antihistamines; apoptosis; asthma; cytokines; eosinophils;histamine H1-receptor antagonists; levocetirizine Document Type: Research article DOI: 10.2500/aap2007.28.3045 Affiliations: 1: From The Immunopharmacology Research Group, Medical School, University of Tampere, Tampere, Finland, and , the Research Unit and 2: From The Immunopharmacology Research Group, Medical School, University of Tampere, Tampere, Finland, and , Department of Respiratory Medicine, Tampere University Hospital, Tampere, Finland Publication date: 2007-09-01

Levocetirizine is the pharmacologically active enantiomer of cetirizine. It is a potent histamine H-1 receptor antagonist with anti-inflammatory and antiallergic properties. The review analyses the levocetirizines properties in terms of safety and efficacy both in allergic rhinitis and urticarioid syndromes. Keywords: allergic rhinitis, chronic idiopatic urticaria, levocetirizine
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Levocetirizine (R-cetirizine), or (R)-[2-[4-[(4-chlorophenyl)phenylmethyl]-1piperazinyl]ethoxy]acetic acid dihydrochloride is the pharmacologically active enantiomer of cetirizine, and is a potent histamine H-1 receptor antagonist.1Cetirizine consists of a racemic mixture of R- and S-cetirizine. The two enantiomers differ as to pharmacological activity, bond affinity to the H-1 receptor, and dissociation constant. Various studies agree in attributing all pharmacological activity, higher bond affinity, and longer dissociation half-life to Rcetirizine.2 These characteristics make levocetirizine an excellent pseudo-irreversible antagonist of the H-1 receptor, and one that is not as easily displaced by histamine as cetirizine on the H-1 receptor in vivo. The high power and specificity of levocetirizine as inverse agonist for the H1 receptor3 have been demonstrated both at the level of endothelial cells and of smooth muscle fibrocells of blood microcirculation.4 On these sites the antagonism of histamine is responsible for the inhibition of the increase in vascular permeability and vasodilation. Inhibition of edema formation and mucus secretion represent the result of levocetitizine effects on skin and respiratory mucosa, respectively. These pharmacological actions underlie the therapeutic effect of levocetirizine in urticaria and rhinitis. Levocetirizine also has several other pharmacological effects partially related to its antagonism on the H-1. T lymphocytes, dendritic cells and lung macrophages express the histamine H-1 receptor on their cell surface which induces the expression of activation molecules and the synthesis of cytokines and chemokines with proinflammatory effects when activated.5 Triggiani and colleagues have recently demonstrated that levocetirizine can inhibit the synthesis of IL-6 from human lung macrophages and histamine-induced production of IL-8 by dendritic cells.6 The inhibiting effects of levocetirizine have also been studied on keratinocytes, where it blocks the secretion of chemokines and GM-CSF.7 Additionally, recent studies have shown that levocetirizine reduces the expression of activation molecules (CD134 and ICAM-1) and of a transcription factor involved in the differentiation of Th2 lymphocytes (GATA-3).8 The inhibition of the NF- B transcription factor complex induced by levocetirizine suppresses the endothelial production of eotaxin, IL-1 , TNF- and VCAM-1 stimulated by histamine.9 Lastly, levocetirizine significantly inhibits both eotaxin-induced eosinophil transendothelial migration10 and endothelial adhesion,11 and modulates the release (at a concentration of 1 nM) of proinflammatory cytokines such as IL-1 and IL-7 by liposaccharide-activated eosinophils, at the same time increasing the tissue inhibitors of metalloproteinase-1 and -4 and of matrix metalloproteinase-9.12 The latter anti-inflammatory and antiallergic properties are expressions of other pharmacological activities of levocetirizine9 not strictly correlated to its receptor antagonist action. Levocetirizine has been shown to have these properties at plasma concentrations between 10 and 500 nM,9,10 which is the range comprising the molecules plasma concentration ( 400 nM) during

a standard treatment at a dose of 5 mg.13 Other second generation antihistamines showed the same effects that were present only in vitro and at pharmacological concentrations unattainable in vivo.14 An innovative concept, which has emerged from the latest studies on levocetirizine, is that there may be a positive interaction between the anti-inflammatory effects and H-1 receptor antagonism. This hypothesis is based on the observation that H-1 is a highly dynamic receptor, whose expression on anti-inflammatory cells may be rapidly modulated (increased or inhibited). Recent data indicate that some cytokines (TNF- , IL-8, IL-13) or growth factors (GM-CSF) can enhance the H-1 receptors expression on monocytes, macrophages and dendritic cells.15,16 By inhibiting the production of the cytokines and growth factors mentioned above, as well as the recruitment of the cells involved in allergic immunophlogosis, the pharmacological blockage of H-1 and H-2 cell receptors by levocetirizine might modify the pathogenesis and clinical evolution of allergic diseases.16 If verified in vivo, this hypothesis could provide the basis for an effective synergy between anti-inflammatory action and H-1 receptor antagonism.