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Eosinophil

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Eosinophils,sometimes calledeosinophilesor, less commonly,acidophils,are a variety ofwhite blood cellsand one of theimmune systemcomponents responsible for combating multicellularparasitesand certaininfectionsinvertebrates.[2]Along withmast cellsandbasophils,they also control mechanisms associated withallergyandasthma.They aregranulocytesthat develop duringhematopoiesisin thebone marrowbefore migrating into blood, after which they are terminally differentiated and do not multiply.[3]

Eosinophil
3D rendering of eosinophil
Eosinophil under the microscope (400×) from a peripheralblood smear.Red blood cellssurround the eosinophil, twoplateletsat the top left corner.
Details
Pronunciation/ˌiːoʊˈsɪnəfɪl/)[1]
SystemImmune system
Identifiers
MeSHD004804
THH2.00.04.1.02017
FMA62861
Anatomical terms of microanatomy

Thesecellsareeosinophilicor "acid-loving "due to their large acidophilic cytoplasmic granules, which show their affinity for acids by their affinity tocoal tar dyes:Normallytransparent,it is this affinity that causes them to appear brick-red afterstainingwitheosin,a reddye,using theRomanowsky method.[4]The staining is concentrated in smallgranuleswithin the cellularcytoplasm,which contain many chemical mediators, such aseosinophil peroxidase,ribonuclease(RNase),deoxyribonucleases(DNase),lipase,plasminogen,andmajor basic protein.These mediators are released by a process calleddegranulationfollowing activation of the eosinophil, and aretoxicto both parasite and host tissues.

In normal individuals, eosinophils make up about 1–3% of white blood cells, and are about 12–17micrometresin size with bilobed nuclei.[3][5]While eosinophils are released into the bloodstream, they reside in tissue.[4]They are found in themedullaand the junction between thecortexand medulla of thethymus,and, in the lowergastrointestinaltract,ovaries,uterus,spleen,prostate,andlymph nodes,but not in thelungs,skin,esophagus,or some other internal organs[vague]under normal conditions. The presence of eosinophils in these latter organs is associated with disease. For instance, patients with eosinophilic asthma have high levels of eosinophils that lead to inflammation and tissue damage, making it more difficult for patients to breathe.[6][7]Eosinophils persist in the circulation for 8–12 hours, and can survive in tissue for an additional 8–12 days in the absence of stimulation.[8]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.[9]

Development

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Blood cell lineage

TH2andILC2cells both express the transcription factorGATA-3,which promotes the production of TH2 cytokines, including the interleukins (ILs).[6]IL-5controls the development of eosinophils in the bone marrow, as they differentiate from myeloid precursor cells.[6][10][11][12]Their lineage fate is determined by transcription factors, including GATA and C/EBP.[3]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 ofhelminthinfection in response tochemokineslikeCCL11(eotaxin-1),CCL24(eotaxin-2), CCL5 (RANTES),5-hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid,and certainleukotrieneslikeleukotriene B4(LTB4) and MCP1/4.Interleukin-13,another TH2 cytokine, primes eosinophilic exit from the bone marrow by lining vessel walls with adhesion molecules such as VCAM-1 and ICAM-1.[6] When eosinophils are activated, they undergo cytolysis, where the breaking of the cell releases eosinophilic granules found in extracellular DNA traps.[6]High concentrations of these DNA traps are known to cause cellular damage, as the granules they contain are responsible for the ligand-induced secretion of eosinophilic toxins which cause structural damage.[6]There is evidence to suggest that eosinophil granule protein expression is regulated by the non-coding RNAEGOT.[13]

Function

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Histology of an eosinophil withinepithelium,characterized by its bilobed nucleus despite scant visible eosinophilic cytoplasm.

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

There are also eosinophils that play a role in fighting viral infections, which is evident from the abundance ofRNasesthey contain within their granules, and infibrinremoval duringinflammation.Eosinophils, along withbasophilsandmast cells,are important mediators ofallergic responsesandasthmapathogenesisand are associated with disease severity. They also fighthelminth(worm) colonization and may be slightly elevated in the presence of certain parasites. Eosinophils are also involved in many other biological processes, including postpubertalmammary glanddevelopment,oestrus cycling,allograftrejection andneoplasia.[21]They have also been implicated inantigen presentationtoT cells.[22]

Eosinophils are responsible for tissue damage and inflammation in many diseases, including asthma.[6][7]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.[7]

An accumulation of eosinophils in thenasal mucosais considered a major diagnostic criterion forallergic rhinitis(nasal allergies).

Granule proteins

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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.[23]These include:

Major basic protein, eosinophil peroxidase, and eosinophil cationic protein are toxic to many tissues.[21]Eosinophil cationic protein and eosinophil-derivedneurotoxinareribonucleaseswithantiviralactivity.[24]Major basic protein induces mast cell andbasophildegranulation, and is implicated inperipheral nerveremodelling.[25][26]Eosinophil cationic protein creates toxic pores in the membranes of target cells, allowing potential entry of other cytotoxic molecules to the cell,[27]can inhibitproliferationofT cells,suppressantibodyproduction byB cells,induce degranulation bymast cells,and stimulate fibroblast cells to secrete mucus andglycosaminoglycans.[28]Eosinophil peroxidase formsreactive oxygen speciesandreactive nitrogen intermediatesthat promoteoxidative stressin the target, causing cell death byapoptosisandnecrosis.[21]

Clinical significance

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Blood count

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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.[29]

Eosinophilia

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Main article:Eosinophilia

An increase in eosinophils, i.e., the presence of more than 500 eosinophils/microlitre of blood is called aneosinophilia,and is typically seen in people with a parasitic infestation of theintestines;autoimmuneandcollagen vascular disease(such asrheumatoid arthritis) andSystemic lupus erythematosus;malignantdiseases such aseosinophilic leukemia,clonal hypereosinophilia,andHodgkin lymphoma;lymphocyte-variant hypereosinophilia;extensiveskindiseases (such as exfoliativedermatitis);Addison's diseaseand other causes of lowcorticosteroidproduction (corticosteroids suppress blood eosinophil levels);reflux esophagitis(in which eosinophils will be found in the squamous epithelium of the esophagus) andeosinophilic esophagitis;and with the use of certaindrugssuch aspenicillin.But, perhaps the most common cause for eosinophilia is an allergic condition such as asthma. In 1989, contaminatedL-tryptophansupplements caused a deadly form of eosinophilia known aseosinophilia-myalgia syndrome,which was reminiscent of thetoxic oil syndromein Spain in 1981.

Reference ranges for blood testsof white blood cells, comparing eosinophil granulocyte amount (shown in light red) with other cells

Eosinophils play an important role in asthma as the number of accumulated eosinophils corresponds to the severity of asthmatic reaction.[7]Eosinophilia in mice models are shown to be associated with high interleukin-5 levels.[7]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.[7]The infiltration of eosinophils at these high concentrations causes an inflammatory reaction.[7]This ultimately leads to airway remodelling and difficulty of breathing.[7]

Eosinophils can also cause tissue damage in the lungs of asthmatic patients.[7]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.[7]

Treatment

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

Monoclonal antibodies such asdupilumabandlebrikizumabtarget 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.[30][31]Mepolizumabandbenralizumabare other treatment options that target the alpha subunit of theIL-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.[32][33]Lysosomotropic agents are an efficient means to target the lysosome-like eosinophil granules inducing eosinophil apoptosis.[34]

Animal studies

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Within the fat (adipose) tissue ofCCR2deficientmice,there is an increased number of eosinophils, greater alternativemacrophageactivation, and a propensity towards type 2cytokineexpression. Furthermore, this effect was exaggerated when the mice becameobesefrom a high fat diet.[35] Mouse models of eosinophilia from mice infected withT. canisshowed an increase in IL-5mRNAin mice spleen.[7]Mouse models of asthma from OVA show a higherTH2response.[6]When mice are administered IL-12 to induce theTH1response, the TH2 response becomes suppressed, showing that mice without TH2 cytokines are significantly less likely to express asthma symptoms.[6]

See also

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References

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  1. ^"eosinophil - Definition of eosinophil in English by Oxford Dictionaries".Oxford Dictionaries - English.Archived fromthe originalon 8 February 2018.Retrieved27 March2018.
  2. ^"What is an Eosinophil? | Definition & Function | CCED".www.cincinnatichildrens.org.Retrieved14 June2018.
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  31. ^Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z, Mosesova S, Eisner MD, Bohen SP, Matthews JG (September 2011)."Lebrikizumab treatment in adults with asthma".The New England Journal of Medicine.365(12): 1088–98.doi:10.1056/nejmoa1106469.PMID21812663.
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  35. ^Bolus WR, Gutierrez DA, Kennedy AJ, Anderson-Baucum EK, Hasty AH (October 2015)."CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue".Journal of Leukocyte Biology.98(4): 467–77.doi:10.1189/jlb.3HI0115-018R.PMC4763864.PMID25934927.Archived fromthe originalon 9 May 2017.Retrieved8 September2016.
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