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      Bidirectional Mast Cell–Eosinophil Interactions in Inflammatory Disorders and Cancer

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          Abstract

          Human mast cells (MCs) and eosinophils were first described and named by Paul Ehrlich. These cells have distinct myeloid progenitors and differ morphologically, ultrastructurally, immunologically, biochemically, and pharmacologically. However, MCs and eosinophils play a pivotal role in several allergic disorders. In addition, these cells are involved in autoimmune disorders, cardiovascular diseases, and cancer. MCs are distributed throughout all normal human tissues, whereas eosinophils are present only in gastrointestinal tract, secondary lymphoid tissues, and adipose tissue, thymus, mammary gland, and uterus. However, in allergic disorders, MCs and eosinophils can form the “allergic effector unit.” Moreover, in several tumors, MCs and eosinophils can be found in close proximity. Therefore, it is likely that MCs have the capacity to modulate eosinophil functions and vice versa. For example, interleukin 5, stem cell factor, histamine, platelet-activating factor (PAF), prostaglandin D 2 (PGD 2), cysteinyl leukotrienes, and vascular endothelial growth factors (VEGFs), produced by activated MCs, can modulate eosinophil functions through the engagement of specific receptors. In contrast, eosinophil cationic proteins such as eosinophil cationic protein and major basic protein (MBP), nerve growth factor, and VEGFs released by activated eosinophils can modulate MC functions. These bidirectional interactions between MCs and eosinophils might be relevant not only in allergic diseases but also in several inflammatory and neoplastic disorders.

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          Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial

          Benralizumab is a humanised, afucosylated, anti-interleukin-5 receptor α monoclonal antibody that induces direct, rapid, and nearly complete depletion of eosinophils. We aimed to assess the efficacy and safety of benralizumab as add-on therapy for patients with severe, uncontrolled asthma and elevated blood eosinophil counts.
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            Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial

            Eosinophilia is associated with worsening asthma severity and decreased lung function, with increased exacerbation frequency. We assessed the safety and efficacy of benralizumab, a monoclonal antibody against interleukin-5 receptor α that depletes eosinophils by antibody-dependent cell-mediated cytotoxicity, for patients with severe, uncontrolled asthma with eosinophilia.
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              Type 2 innate lymphoid cells control eosinophil homeostasis

              Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago, 1 and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins, mediate eosinophil development and survival, 2 and tissue recruitment, 3 respectively, the processes underlying the basal regulation of these signals remain unknown. Here, we show that serum IL-5 is maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, 4 ILC2 co-express IL-5 and IL-13, which is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide (VIP) also stimulates ILC2 through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/402335
                URI : http://frontiersin.org/people/u/392297
                URI : http://frontiersin.org/people/u/458063
                URI : http://frontiersin.org/people/u/428481
                URI : http://frontiersin.org/people/u/45352
                URI : http://frontiersin.org/people/u/147729
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                24 July 2017
                2017
                : 4
                : 103
                Affiliations
                [1] 1Department of Translational Medical Sciences (DiSMeT), Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II , Naples, Italy
                [2] 2Pharmacology and Experimental Therapeutics Unit, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem , Jerusalem, Israel
                [3] 3Department of Public Health, University of Naples Federico II, Monaldi Hospital Pharmacy , Naples, Italy
                [4] 4Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR) , Naples, Italy
                Author notes

                Edited by: Florence Emmanuelle Roufosse, Free University of Brussels, Belgium

                Reviewed by: Josiane Sabbadini Neves, Federal University of Rio de Janeiro, Brazil; Wei Li, Marshall University, United States

                *Correspondence: Francesca Levi-Schaffer, francescal@ 123456ekmd.huji.ac.il ; Gianni Marone, marone@ 123456unina.it

                Specialty section: This article was submitted to Hematology, a section of the journal Frontiers in Medicine

                Article
                10.3389/fmed.2017.00103
                5523083
                28791287
                7b4454e9-4454-430d-8b58-3d95a9418217
                Copyright © 2017 Galdiero, Varricchi, Seaf, Marone, Levi-Schaffer and Marone.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 March 2017
                : 26 June 2017
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 224, Pages: 13, Words: 12268
                Categories
                Medicine
                Review

                allergy,asthma,cancer,eosinophils,inflammation,mast cells,mastocytosis

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