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

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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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          Most cited references 9

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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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            World Health Organization-defined eosinophilic disorders: 2014 update on diagnosis, risk stratification, and management.

             Jason Gotlib (2014)
            The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage. Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1,500/mm(3) and may be associated with tissue damage. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of morphologic review of the blood and marrow, standard cytogenetics, fluorescent in situ hybridization, flow immunocytometry, and T-cell clonality assessment to detect histopathologic or clonal evidence for an acute or chronic myeloid or lymphoproliferative disorder. Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2008 World Health Organization establishes a semimolecular classification scheme of disease subtypes including "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1', chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS), lymphocyte-variant HE, and idiopathic hypereosinophilic syndrome (HES), which is a diagnosis of exclusion. The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1,500/mm(3)) without symptoms or signs of organ involvement, a watch and wait approach with close-follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES. Hydroxyurea and interferon-alpha have demonstrated efficacy as initial treatment and steroid-refractory cases of HES. In addition to hydroxyurea, second-line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms of HES and CEL with outcomes reported for limited number of patients. Although clinical trials have been performed with anti-IL-5 (mepolizumab) and anti-CD52 (alemtuzumab) antibodies, their therapeutic role in primary eosinophilic diseases and HES has yet to be established. Copyright © 2014 Wiley Periodicals, Inc.
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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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                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
                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
                Article
                10.5415/apallergy.2020.10.e24
                7402945
                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.

                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

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