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      Hypereosinophilic syndrome with abundant Charcot-Leyden crystals in spleen and lymph nodes

      case-report

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          Abstract

          Hypereosinophilic syndrome, which is characterized by eosinophilia in the peripheral blood, often causes various organ disorders. Charcot-Leyden crystals are recognized features of various diseases, such as parasite infection and asthma, and are known to be classic hallmarks of eosinophilic inflammation. Our recent study revealed the mechanism of Charcot-Leyden crystal formation (i.e., galectin-10 crystallization), namely the involvement of eosinophil extracellular trap cell death, a nonapoptotic cell death. Here we report an autopsy case of a 57-year-old man who had died of hypereosinophilic syndrome. We found numerous eosinophil extracellular trap cell death-associated Charcot-Leyden crystals in the spleen and lymph nodes. Observation of abdominal lymph nodes by electron microscopy revealed eosinophil extracellular traps and free extracellular granules, which are characteristic of typical eosinophil extracellular trap cell death. In this case, we observed various sizes of Charcot-Leyden crystals that were stained with anti-galectin-10 immunofluorescent staining. Further studies are required to understand the pathophysiological roles of Charcot-Leyden crystals and these may lead to the development of novel therapeutic modalities for severe eosinophilic inflammation.

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          Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans.

          Eosinophils release their granule proteins extracellularly through exocytosis, piecemeal degranulation, or cytolytic degranulation. Findings in diverse human eosinophilic diseases of intact extracellular eosinophil granules, either free or clustered, indicate that eosinophil cytolysis occurs in vivo, but the mechanisms and consequences of lytic eosinophil degranulation are poorly understood. We demonstrate that activated human eosinophils can undergo extracellular DNA trap cell death (ETosis) that cytolytically releases free eosinophil granules. Eosinophil ETosis (EETosis), in response to immobilized immunoglobulins (IgG, IgA), cytokines with platelet activating factor, calcium ionophore, or phorbol myristate acetate, develops within 120 minutes in a reduced NADP (NADPH) oxidase-dependent manner. Initially, nuclear lobular formation is lost and some granules are released by budding off from the cell as plasma membrane-enveloped clusters. Following nuclear chromatolysis, plasma membrane lysis liberates DNA that forms weblike extracellular DNA nets and releases free intact granules. EETosis-released eosinophil granules, still retaining eosinophil cationic granule proteins, can be activated to secrete when stimulated with CC chemokine ligand 11 (eotaxin-1). Our results indicate that an active NADPH oxidase-dependent mechanism of cytolytic, nonapoptotic eosinophil death initiates nuclear chromatolysis that eventuates in the release of intact secretion-competent granules and the formation of extracellular DNA nets.
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            Protein crystallization promotes type 2 immunity and is reversible by antibody treatment

            Although spontaneous protein crystallization is a rare event in vivo, Charcot-Leyden crystals (CLCs) consisting of galectin-10 (Gal10) protein are frequently observed in eosinophilic diseases, such as asthma. We found that CLCs derived from patients showed crystal packing and Gal10 structure identical to those of Gal10 crystals grown in vitro. When administered to the airways, crystalline Gal10 stimulated innate and adaptive immunity and acted as a type 2 adjuvant. By contrast, a soluble Gal10 mutein was inert. Antibodies directed against key epitopes of the CLC crystallization interface dissolved preexisting CLCs in patient-derived mucus within hours and reversed crystal-driven inflammation, goblet-cell metaplasia, immunoglobulin E (IgE) synthesis, and bronchial hyperreactivity (BHR) in a humanized mouse model of asthma. Thus, protein crystals may promote hallmark features of asthma and are targetable by crystal-dissolving antibodies.
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              Charcot-Leyden crystal formation is closely associated with eosinophil extracellular trap cell death.

              Protein crystallization in human tissue rarely occurs. Charcot-Leyden crystals (CLCs) were described in various eosinophilic diseases over 150 years ago, but our understanding of CLC formation still remains limited. In this study, we demonstrate that CLCs observed in varied inflamed human tissues are closely associated with eosinophil cell-free granules and nuclear envelope/plasma membrane disintegration with release of filamentous chromatin (extracellular traps); typical morphologies of a regulated pathway of extracellular trap cell death (ETosis). During the process of eosinophil ETosis, eccentrically-localized cytoplasmic and perinuclear CLC protein (galectin-10) is homogeneously re-distributed in the cytoplasm. Rapid (1-2 min) formation of intracytoplasmic CLCs was observed using time-lapse imaging. Plasma membrane rupture enabled the release of both intracellularly formed CLCs and soluble galectin-10 that further contributed to formation of CLCs extracellularly, in parallel with the expulsion of free intact granules and extracellular traps. CLC formation and galectin-10 release were dependent on NADPH-oxidase. To our knowledge, this is the first demonstration of natural formation of CLCs in association with an active physiological process (i.e. ETosis). These results indicate that dynamic changes in intracellular localization and release of galectin-10 contribute to CLC formation in vivo, and suggest that CLC/galectin-10 might serve as an indicator of ETosis.
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                Author and article information

                Journal
                Asia Pac Allergy
                Asia Pac Allergy
                APA
                Asia Pacific Allergy
                Asia Pacific Association of Allergy, Asthma and Clinical Immunology
                2233-8276
                2233-8268
                July 2020
                08 July 2020
                : 10
                : 3
                : e24
                Affiliations
                [1 ]Department of Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
                [2 ]Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.
                [3 ]Department of Molecular Pathology and Tumor Pathology, Akita University Graduate School of Medicine, Akita, Japan.
                [4 ]Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
                Author notes
                Correspondence to Shigeharu Ueki. Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita 010-8543, Japan. Tel: +81-18-884-6209, Fax: +81-18-884-6209, shigeharu.ueki@ 123456gmail.com
                Author information
                https://orcid.org/0000-0002-7028-7073
                https://orcid.org/0000-0002-3537-7735
                https://orcid.org/0000-0003-4108-7627
                https://orcid.org/0000-0002-1161-9074
                https://orcid.org/0000-0002-0141-7081
                https://orcid.org/0000-0002-6758-3787
                Article
                10.5415/apallergy.2020.10.e24
                7402945
                ef7537f1-5669-481f-9def-214b5f061f03
                Copyright © 2020. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 04 April 2020
                : 03 July 2020
                Funding
                Funded by: Japan Agency for Medical Research and Development, CrossRef http://dx.doi.org/10.13039/100009619;
                Award ID: 19ek0410055
                Funded by: Charitable Trust Laboratory Medicine Research Foundation of Japan;
                Award ID: JSPS KAKENHI 20K08794
                Award ID: 16K08926
                Award ID: 17K09993
                Categories
                Case Report

                Immunology
                charcot-leyden crystal,galectin-10,etosis,eosinophils,hypereosinophilic syndrome
                Immunology
                charcot-leyden crystal, galectin-10, etosis, eosinophils, hypereosinophilic syndrome

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