Eosinophils are granulocytes derived from bone marrow, specifically arising from hematopoietic CD34⁺ stem cells. As active contributors to the innate and passive immune response against pathogens, specifically parasites (helminths) and viruses, eosinophils can cause an inflammatory cascade producing and releasing chemokines, cytokines, lipid mediators, as well as other growth factors. Once eosinophils mature and leave the bone marrow, they no longer proliferate, but circulate in the blood or migrate to tissues including the thymus, lower GI tract, ovary (during specific phases of the cycle), uterus, spleen and lymph nodes at infection or inflammation sites. They comprise 1–5% of circulating leucocytes, rising to those higher levels only when activated. In peripheral blood, they are found in relatively low numbers surviving from 8–18 hours. However, in an unstimulated state in tissues, they can be found in larger numbers for up to 12 days. Not normally circulating in the lung, on the skin, or in other organs, the presence of eosinophils in any of these locations is usually associated with disease.
With their effector mechanisms, eosinophils persist in the blood and airways and influence tissue function. Asthma, chronic obstructive pulmonary disease (COPD), and some gastrointestinal disorders such as irritable bowel syndrome are related to airway or blood eosinophilia. Individuals with significant eosinophilia are at risk for more severe disease. The ability to identify eosinophil effector mechanisms and surface markers can be closely correlated to the severity of disease and a possible clinical outcome.
Markers for eosinophil maturation
Eosinophils are about 12–17 µm in diameter and distinguished by their bilobed nuclei and an abundance of specific, pink cytoplasmic granules. These granules, composed of cytotoxic cationic proteins, also contain an array of cytokines and chemokines. In mice models of asthma, the lineage of eosinophils is determined by the interplay of transcription factors including CCAAT/enhancer-binding protein (C/EBP), GATA-1, PU.1, and friend of GATA (FOG). Levels of C/EBP and GATA-1 are directed by interactions with PU.1 and FOG. Two additional transcription factors are also involved, Icsbp and Id proteins (Id1 and Id2). The mechanism of action for Icsbp is unknown, but Id1 seems to inhibit eosinophil development where it has been found that Id2 accelerates eosinophil maturation. Because of the spectrum of transcription factors involved during the maturation of eosinophils, they may also influence late-stage differentiation.
Markers for eosinophil activation
The granular proteins released by activated eosinophils are not only toxic to pathogens but can also have a direct toxic effect on tissues. Eosinophils contribute to inflammatory pathways because of their capacity to secrete cytokines and chemokines. Approximately 50% of patients with severe asthma have airway eosinophilia. Measuring the elevated numbers of eosinophils in the airways correlates with tissue biomarkers and the severity of disease.
In the airways of asthmatics, for example, eosinophils produce type-2 factors such as interleukins IL-3, IL-4, IL-5, IL-13, and IL-25. Eosinophils also secrete chemokines such as CCL5, CCL11, and CCL3, which recruit leukocytes to the inflammation site. Following an allergenic challenge and inducing the recruitment of neutrophils, eosinophils express GM-CSF and CXCL8. The three type-2 cytokines—IL-3, IL-5, and GM-CSF—are closely linked and particularly important in initiation and perpetuation of eosinophilic airway inflammation as their receptors share a common β subunit.
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In severe asthma, eosinophils may remodel the airway due to the release of transforming growth factor β-1. Also found to be elevated in the serum of severe asthmatics and behaving as a potent activator for eosinophils is interferon-gamma (IFN-γ), a type-1 cytokine.
Markers for eosinophil migration
Once recruited into the airways, the surface phenotype of eosinophils changes to reflect their transendothelial and transepithelial migration and interactions with tissue and the extracellular matrix. Eosinophils will shed L-selectin, CD31, IL-5, and CD162 receptors and upregulate the function of CD11b, CD11c, CD35, CD44, CD66, and CD81. A few other receptors will appear including HLA-DR, ICAM-1, and CD69. The presence of CD11b is a particular characteristic of airway eosinophil phenotype in asthma, acting as a mediator for adhesion and migration of eosinophils to fibrinogen and other extracellular matrix ligands.
Table of eosinophil markers
The table below lists human and mouse proteins used for phenotyping different populations of eosinophils as recently mentioned in the literature. Accompanying each listed marker are links to relevant antibodies and ELISA kits, as these immunodetection tools are routinely used in cell characterization studies via flow cytometry and immunostaining. The associated products are offered by a variety of manufacturers and can serve as a useful reference for eosinophil immunophenotyping.
Gene | Synonyms | Marker Type | Protein Type | Localization | Size (kDa) | Reference | Antibodies | ELISA Kits |
ANPEP |
CD13 |
Migration |
Enzyme |
Cell Membrane |
109.5 |
2,4 |
ANPEP antibodies |
ANPEP ELISA |
CCL11 |
Eotaxin |
Migration |
Cytokine |
Secreted |
10.7 |
5,6 |
CCL11 antibodies |
CCL11 ELISA |
CCL24 |
Eotaxin-2 |
Migration |
Cytokine |
Secreted |
13.1 |
5,6 |
CCL24 antibodies |
CCL24 ELISA |
CCL26 |
Eotaxin-3 |
Migration |
Cytokine |
Secreted |
10.6 |
5,6 |
CCL26 antibodies |
CCL26 ELISA |
CCR1 |
|
General |
Receptor |
Cell Membrane |
41.2 |
2,5 |
CCR1 antibodies |
CCR1 ELISA |
CCR3 |
CD193 |
General |
Receptor |
Cell Membrane |
41 |
1,2,3,5,6,8 |
CCR3 antibodies |
CCR3 ELISA |
CD34 |
|
Activation |
Adhesion molecule |
Cell Membrane |
40.7 |
1,2,5,6 |
CD34 antibodies |
CD34 ELISA |
CD4 |
|
Maturation, Immunoglobulin |
Receptor |
Cell Membrane |
51.1 |
2,7,8 |
CD4 antibodies |
CD4 ELISA |
CD44 |
|
General, Adhesion |
Receptor |
Cell Membrane |
81.5 |
2,4 |
CD44 antibodies |
CD44 ELISA |
CD45RO* |
CD45 (isoform) |
Migration |
Receptor |
Cell Membrane |
|
2,4 |
CD45RO antibodies |
CD45RO ELISA |
CD48 |
|
Maturation, Immunoglobulin |
Receptor |
Cell Membrane |
27.7 |
2,4 |
CD48 antibodies |
CD48 ELISA |
CD58 |
LFA3 |
Activation, Immunoglobulin |
Receptor |
Cell Membrane |
28.1 |
2,4 |
CD58 antibodies |
CD58 ELISA |
CD63 |
LAMP-3 |
General |
Receptor |
Cell Membrane |
25.6 |
2,4 |
CD63 antibodies |
CD63 ELISA |
CD69 |
CLEC2C |
Activation |
Receptor |
Cell Membrane |
22.6 |
2,4 |
CD69 antibodies |
CD69 ELISA |
CD80 |
B7-1 |
Activation |
Receptor |
Cell Membrane |
33 |
2,3 |
CD80 antibodies |
CD80 ELISA |
CD81 |
|
Migration |
Receptor |
Cell Membrane |
25.8 |
2,5 |
CD81 antibodies |
CD81 ELISA |
CD86 |
B7-2 |
Activation |
Receptor |
Cell Membrane |
37.7 |
2,5 |
CD86 antibodies |
CD86 ELISA |
CEACAM8 |
CD66b |
Migration |
Receptor |
Cell Membrane |
38.1 |
1,4,7 |
CEACAM8 antibodies |
CEACAM8 ELISA |
CEBP |
C/EBPs |
Maturation |
Transcription FActor |
Nucleus |
37.6 |
5,6 |
CEBPB antibodies |
CEBPB ELISA |
CR1 |
CD35 |
Migration, Complement |
Receptor |
Cell Membrane |
|
2,4 |
CR1 antibodies |
CR1 ELISA |
CSF2 |
GM-CSF |
Activation |
Cytokine |
Secreted |
16.3 |
2,3,5,8 |
CSF2 antibodies |
CSF2 ELISA |
CXCL8 |
IL8 |
Activation |
Cytokine |
Secreted |
11.1 |
5,8 |
CXCL8 antibodies |
CXCL8 ELISA |
CXCR2 |
CD182, IL8RB |
Activation |
Receptor |
Cell Membrane |
40.8 |
2,8 |
CXCR2 antibodies |
CXCR2 ELISA |
CXCR3 |
CD183 |
General |
Receptor |
Cell Membrane |
40.7 |
2,8 |
CXCR3 antibodies |
CXCR3 ELISA |
CYSLTR1 |
CysLT1 |
Lipid mediator |
Receptor |
Cell Membrane |
38.5 |
2,5 |
CYSLTR1 antibodies |
CYSLTR1 ELISA |
FCAR |
FcαR1, CD89 |
Activation, Immunoglobulin |
Receptor |
Cell Membrane |
32.3 |
2,4 |
CD89 antibodies |
CD89 ELISA |
FCGR3A |
CD16, FcyRIII |
Maturation, Immunoglobulin |
Receptor |
Cell Membrane |
29.1 |
2,4,7 |
FCGR3A antibodies |
FCGR3A ELISA |
GATA1 |
|
Activation |
Transcription FActor |
Nucleus |
42.8 |
5,6 |
GATA1 antibodies |
GATA1 ELISA |
HLA-DR* |
|
Activation, Immunoglobulin |
Receptor, Multi-gene |
Cell Membrane |
|
2,3,4,5 |
HLA-DR antibodies |
HLA-DR ELISA |
ICAM1 |
CD54 |
Activation, Immunoglobulin |
Receptor |
Cell Membrane |
57.8 |
2,4 |
ICAM1 antibodies |
ICAM1 ELISA |
IFNG |
IFN gamma |
Activation |
Cytokine |
Secreted |
19.3 |
2,6 |
IFNG antibodies |
IFNG ELISA |
IL13 |
|
Activation |
Cytokine |
Secreted |
15.8 |
2,5,6,7 |
IL13 antibodies |
IL13 ELISA |
IL17RA |
CD217 |
Activation |
Receptor |
Cell Membrane |
96.1 |
4,5,8 |
IL17RA antibodies |
IL17RA ELISA |
IL3 |
Interleukin 3 |
Activation |
Cytokine |
Secreted |
17.2 |
2,5 |
IL3 antibodies |
IL3 ELISA |
IL33 |
|
Migration |
Cytokine |
Secreted |
30.8 |
5,8 |
IL33 antibodies |
IL33 ELISA |
IL3RA |
CD123 |
Activation |
Receptor |
Cell Membrane |
39.1 |
1,4 |
CD123 antibodies |
CD123 ELISA |
IL4 |
Interleukin 4 |
Activation |
Cytokine |
Secreted |
17.5 |
2,5,7 |
IL4 antibodies |
IL4 ELISA |
IL5 |
|
General |
Cytokine |
Secreted |
15.2 |
2,3,5,6,7,8 |
IL5 antibodies |
IL5 ELISA |
IL5RA |
CD125 |
Activation |
Receptor |
Cell Membrane |
47.7 |
1,4,5,6 |
IL5RA antibodies |
IL5RA ELISA |
IL6 |
Interleukin 6 |
Activation |
Cytokine |
Secreted |
23.7 |
2,5,8 |
IL6 antibodies |
IL6 ELISA |
ITGA4 |
CD49d, VLA-4 |
Activation, Adhesion |
Receptor |
Cell Membrane |
114.9 |
1,5 |
CD49d antibodies |
CD49d ELISA |
ITGAL |
CD11a, αL integrin |
Migration, Adhesion |
Receptor |
Cell Membrane |
128.8 |
2,4 |
CD11a antibodies |
CD11a ELISA |
ITGAM |
CD11b, αM integrin |
Migration, Adhesion |
Receptor |
Cell Membrane |
127.2 |
2,3,4,5 |
ITGAM antibodies |
ITGAM ELISA |
ITGAX |
CD11c, αX integrin |
Migration, Adhesion |
Receptor |
Cell Membrane |
127.8 |
2,3,4 |
CD11c antibodies |
CD11c ELISA |
ITGB1 |
CD29 |
Activation, Adhesion |
Receptor |
Cell Membrane |
86.4 |
2,4,5 |
ITGB1 antibodies |
ITGB1 ELISA |
ITGB2 |
CD18, β₂ integrin |
Activation, Adhesion |
Receptor |
Cell Membrane |
84.8 |
2,4,5 |
ITGB2 antibodies |
ITGB2 ELISA |
KLRB1 |
CD161 |
Activation |
Receptor |
Cell Membrane |
25.4 |
2,7 |
CD161 antibodies |
CD161 ELISA |
LTA |
TNFB |
Activation |
Cytokine |
Cell Membrane, Secreted |
22.3 |
2,5 |
LTA antibodies |
LTA ELISA |
LTB4R |
|
Lipid mediator |
Receptor |
Cell Membrane |
37.6 |
2,8 |
LTB4R antibodies |
LTB4R ELISA |
MHC class II* |
MHC-II |
Activation |
Multi-subunit complex, Receptor |
Cell Membrane |
|
3,5 |
MHC Class II antibodies |
MHC Class II ELISA |
MMP9 |
|
Activation |
Enzyme |
Secreted |
78.5 |
5,8 |
MMP9 antibodies |
MMP9 ELISA |
PTPRC |
CD45, LCA, B220 |
Migration |
Receptor |
Cell Membrane |
147.5 |
2,3,4 |
CD45 antibodies |
CD45 ELISA |
SELL |
CD62L, L-selectin |
General, Migration, Adhesion |
Receptor |
Cell Membrane |
42.2 |
1,2,4 |
CD62L antibodies |
CD62L ELISA |
SELP |
P-selectin, CD62P |
Activation, Adhesion |
Receptor |
Cell Membrane |
90.8 |
4,5 |
SELP antibodies |
SELP ELISA |
SELPLG |
CD162 |
General, Adhesion |
Receptor |
Cell Membrane |
43.2 |
2,4,5 |
CD162 antibodies |
CD162 ELISA |
SIGLEC8 |
|
Activation |
Receptor |
Cell Membrane |
54 |
1,2,5 |
SIGLEC8 antibodies |
SIGLEC8 ELISA |
SPI1 |
PU.1 |
Activation |
Transcription factor |
Nucleus |
31.1 |
5,6 |
PU.1 antibodies |
PU.1 ELISA |
TLR2 |
CD282 |
Activation, TLR |
Receptor |
Cell Membrane |
89.8 |
2,5 |
TLR2 antibodies |
TLR2 ELISA |
TLR4 |
CD284 |
Activation, TLR |
Receptor |
Cell Membrane |
95.7 |
2,5 |
TLR4 antibodies |
TLR4 ELISA |
TLR9 |
|
Activation, TLR |
Receptor |
Cell Membrane |
115.9 |
2,5 |
TLR9 antibodies |
TLR9 ELISA |
TNF |
TNF-alpha, TNFa |
Activation |
Receptor |
Cell Membrane |
25.6 |
2,5,8 |
TNF alpha antibodies |
TNF alpha ELISA |
TNFRSF9 |
CD137 |
Migration |
Receptor |
Cell Membrane |
27.9 |
2,4 |
TNFRSF9 antibodies |
TNFRSF9 ELISA |
FOG* |
Friend of GATA |
Maturation |
Transcription factor |
Nucleus |
|
6 |
|
|
ID1 |
|
Maturation |
Transcription factor |
Nucleus |
|
6 |
|
|
Note: *Some proteins are protein isoforms or multi-subunit protein complexes composed of several distinct genes. Information on Protein Type, Localization, and Size (kDa) obtained from UniProt.org (for human genes only).
Other eosinophil markers
A surface structure that is completely unique to human eosinophils is ADGRE1 (EMR1), a type of adhesion GPCR. Other cell surface markers such as CCR3, CRth2, IL-5 receptor and Siglec-8 are expressed somewhat specifically on eosinophils, but also on mast cells and basophils. Activation of eosinophils to secrete IL-5 may be mediated by complexing with IgE and other mechanisms. Although the mechanism is not understood, an increase of IL-5, GM-CSF, and CCL5 in sputum can be found in COPD patients with eosinophilia. This reaction, however, may be more definitively linked to associated allergies or asthma.
Eosinophils release multiple growth factors that promote airway remodeling and are known to produce TGF-β in disease states involving the skin (atopy), nose (nasal polyposis), and blood (idiopathic hypereosinophilic syndrome). Eosinophils have been discovered as the main source of TGF-β in bronchial biopsies removed from asthmatic patients. In addition, eosinophils stimulate epithelial cells to produce several mediators, including TGF-β which is also implicated in tissue remodeling.
Another potential explanation for persistent airway eosinophilia in patients with severe eosinophilic asthma is the maturation of CD34⁺ and IL-5Rα progenitors in lieu of recruitment of mature cells. IL-5 seems to govern this activity and also play a role in stimulating bone marrow production and release of eosinophils, which are subsequently recruited to the tissues by P-selectin.
References
1. Hassani M, van Staveren S, van Grinsven E, et al. Characterization of the phenotype of human eosinophils and their progenitors in the bone marrow of healthy individuals. Haematologica. 2020;105(2):e52-e56. Published 2020 Jan 31. doi:10.3324/haematol.2019.219048
2. Carr TF, Berdnikovs S, Simon HU, Bochner BS, Rosenwasser LJ. Eosinophilic bioactivities in severe asthma. World Allergy Organ J. 2016;9:21. Published 2016 Jun 27. doi:10.1186/s40413-016-0112-5
3. Xenakis JJ, Howard ED, Smith KM, et al. Resident intestinal eosinophils constitutively express antigen presentation markers and include two phenotypically distinct subsets of eosinophils. Immunology. 2018;154(2):298-308. doi:10.1111/imm.12885
4. Johansson MW. Eosinophil Activation Status in Separate Compartments and Association with Asthma. Front Med (Lausanne). 2017;4:75. Published 2017 Jun 12. doi:10.3389/fmed.2017.00075
5. McBrien CN, Menzies-Gow A. The Biology of Eosinophils and Their Role in Asthma. Front Med (Lausanne). 2017;4:93. Published 2017 Jun 30. doi:10.3389/fmed.2017.00093
6. Uhm TG, Kim BS, Chung IY. Eosinophil development, regulation of eosinophil-specific genes, and role of eosinophils in the pathogenesis of asthma. Allergy Asthma Immunol Res. 2012;4(2):68-79. doi:10.4168/aair.2012.4.2.68
7. Nguyen T, Gernez Y, Fuentebella J, et al. Immunophenotyping of peripheral eosinophils demonstrates activation in eosinophilic esophagitis. J Pediatr Gastroenterol Nutr. 2011;53(1):40-47. doi:10.1097/MPG.0b013e318212647a
8. Barnes PJ. Inflammatory endotypes in COPD. Allergy. 2019;74(7):1249-1256. doi:10.1111/all.13760