Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Metcalfe, D. D., R. Pawankar, S. J. Ackerman, C. Akin, F. Clayton, F. H. Falcone, G. J. Gleich, et al. 2016. “Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases.” The World Allergy Organization Journal 9 (1): 7. doi:10.1186/s40413-016-0094-3. http://dx.doi.org/10.1186/ s40413-016-0094-3. Published Version doi:10.1186/s40413-016-0094-3 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:25658402 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Metcalfe et al. World Allergy Organization Journal (2016) 9:7 DOI 10.1186/s40413-016-0094-3 REVIEW Open Access Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases Dean D. Metcalfe1*, Ruby Pawankar2, Steven J. Ackerman3, Cem Akin4, Frederic Clayton5, Franco H. Falcone6, Gerald J. Gleich7, Anne-Marie Irani8, Mats W. Johansson9, Amy D. Klion10, Kristin M. Leiferman11, Francesca Levi-Schaffer12, Gunnar Nilsson13, Yoshimichi Okayama14, Calman Prussin1, John T. Schroeder15, Lawrence B. Schwartz16, Hans-Uwe Simon17, Andrew F. Walls18 and Massimo Triggiani19 Abstract Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology. Introduction phases of the innate immune response, promote the Eosinophils, mast cells and basophils are major ef- recruitment of other inflammatory cells and partici- fector cells of innate immunity and play a funda- pate in the initiation and regulation of adaptive im- mental role in the mechanisms of defense against munity. Eosinophils and basophils are recruited bacterial, viral and parasitic infections. These cells within organs and tissues following inflammatory are distinct in terms of development, maturation and and chemotactic stimuli that are produced by in- location within tissues. Eosinophils and basophils flammation. Mast cells, eosinophils and basophils are fully mature in the bone marrow and under physio- therefore activated simultaneously in many diseases logical circumstances circulate as blood cells. Mast including infections, allergic and autoimmune disor- cells leave the bone marrow as progenitors and ders and cancer. Investigation of the role and func- reach their final maturation within peripheral tissues. tion of mast cells, eosinophils and basophils in However, these three types of cells are often involved human disease has been hampered by difficulties in together in a variety of pathological conditions when obtaining cells from human sources in sufficient they are activated and accumulate in inflamed tissues number to perform suitable in vitro studies. Mature where they release a wide spectrum of chemical me- human mast cells can be retrieved only from tissues diators of inflammation. whereas eosinophils and basophils circulate in the Given their strategic location at the major body surfaces blood in low numbers. Fortunately, new and efficient including the skin and the lining of the lung and gastro- methods to purify these cells from human blood and intestinal tract, mast cells are among the first cells to tissues have been developed and now allow reprodu- recognize danger signals coming from the external environ- cible studies to explore their role in various patho- ment. Once activated, mast cells help orchestrate the early physiological conditions. At the same time, highly sensitive techniques are now available to measure * Correspondence: [email protected] mediators and to detect cell surface molecules, even 1Laboratory of Allergic Diseases, National Institute of Allergy and Infectious from limited number of cells. These major improve- Diseases, National Institutes of Health, Bethesda, MD 20892, USA ments in cell purification, flow cytometry and Full list of author information is available at the end of the article © 2016 Metcalfe et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Metcalfe et al. World Allergy Organization Journal (2016) 9:7 Page 2 of 15 mediator measurement have contributed to the iden- epitope correlates inversely with lung function in non- tification of molecules that are either released from severe asthma, i.e., higher N29 reactivity is associated with or expressed on the surface of activated mast cells, lower pulmonary function [1, 2]. In addition, by ROC eosinophils and basophils and have been associated curve analysis, N29 reactivity predicts decreased lung with involvement of these cells in human disease. In function in non-severe asthma [1, 2]. Partially activated β2 some cases, these molecules have provided important integrin correlates with broncheoalveolar lavage (BAL) eo- clues into the mechanisms by which mast cells, eo- sinophilia in patients with mild allergic asthma [1, 2]. sinophils and basophils participate in the develop- CD25 can be upregulated by IL-5 and GM-CSF in vitro ment of human disease. and its expression is increased on BAL eosinophils in eo- sinophilic asthma and tissue eosinophils in atopic derma- Eosinophils titis and EoE [7, 8]. Moreover, HLA-DR expression was Surface markers of activation observed on sputum eosinophils of patients with asthma Recruitment of eosinophils from the circulation to tis- [9]. CD69 and neuropeptide S receptor are up-regulated sues in disease requires that eosinophils become acti- on blood eosinophils in severe disease compared to non- vated [1–3]. Up-regulation, and in some cases down- severe disease (Table 1) [1, 10]. In contrast, CD44 and ac- regulation, of surface proteins on blood eosinophils and tivated β1 integrin are increased in well-controlled/non-se- activated conformations of integrins or Fc receptors have vere, but not in poorly controlled/severe, asthma. This is been associated with aspects of allergic disease (Table 1) suggested to be due to continuous extravasation of the [1–4]. Up-regulation or down-regulation in the table re- high-expressing eosinophils in severe disease [1]. fers to altered cell-surface protein expression regardless The expression of some proteins has been found to of the mechanism, which may be mobilization from change in response to intervention, such as administra- intracellular stores or the result of altered transcription tion of corticosteroids or an anti-IL-5 antibody (Table 2) or translation and may mean a change in average level [1, 6, 7, 11]. Specifically, the expression of β2 integrin is on all cells or a change in the proportion of positive cells decreased by corticosteroids and CCR3 is decreased by [1]. Some studies are on purified eosinophils, whereas anti-IL-5 (in EoE) [6, 11]. Anti-IL-5 causes decreased β2 some are on unfractionated blood cells. The latter has activation and, after segmental lung antigen challenge, advantages, including the requirement for only a small decreased levels of αL, αM, and β2 integrins as well as amount of blood. PSGL-1 (in mild allergic asthma) [1]. The utility of these Several proteins, including CD48, CD137, CRTH2, potential markers, e.g., as predictors of aspects of allergic ICAM-1, IL-25R, integrins, and Fc receptors have been disease or of response to intervention, and differences reported to be up- or down-regulated in one or more and similarities in the behavior of markers among differ- diseases when compared to normal, non-allergic healthy ent allergic diseases, need to be explored further in clin- individuals (Table 1). At least some changes appear ical studies. disease-specific. αX integrin, CRTH2, FcεRII (CD23), and ICAM-1 are up-regulated on eosinophils in eosinophilic Major basic protein eosophagitis (EoE) but not in airway allergies like atopic Major basic protein (MBP)-1 and MBP-2 are two of the asthma or allergic rhinitis [5]; IL-25R is up-regulated in five basic proteins found within secondary eosinophil mild allergic asthma but not in atopic non-asthmatic granules, the others being eosinophil-derived neurotoxin subjects [1]; CD44 and CCR3 are down-regulated in EoE (EDN) also known as ribonuclease (RNase) 2, eosinophil but not in airway allergies [5]. There are conflicting re- cationic protein (ECP) also known as RNase3, and eo- ports in the case of some proteins. Some authors found sinophil peroxidase (EPX) (Table 3) [12]. MBP comprises FcγRIII (CD16) to be up-regulated in airway allergies [1], the crystalloid core of the specific eosinophil granule, ac- whereas others [5] found no change compared to normal counting for a major portion of the eosinophil granule healthy individuals. protein, and has a high isoelectric point, calculated at Expression or activation of some proteins has been greater than pH 11, so strongly basic that it cannot be found to be associated with clinical findings including ex- measured accurately [13].