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      HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33

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          Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine’s activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.

          Graphical Abstract


          • HpARI is a suppressor of IL-33 release and consequent allergic sensitization
          • HpARI binds active IL-33 and nuclear DNA, tethering IL-33 within necrotic cells
          • HpARI is active against both human and murine IL-33


          Osbourn et al identified HpARI, a protein secreted by a helminth parasite that is capable of suppressing allergic responses. HpARI binds to IL-33 (a critical inducer of allergy) and nuclear DNA, preventing the release of IL-33 from necrotic epithelial cells.

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          Most cited references 61

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                Author and article information

                Cell Press
                17 October 2017
                17 October 2017
                : 47
                : 4
                : 739-751.e5
                [1 ]MRC Centre for Inflammation Research, University of Edinburgh, Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
                [2 ]Department of Respiratory, Inflammation and Autoimmunity, MedImmune Ltd, Granta Park, Cambridge CB21 6GH, UK
                [3 ]Institute of Immunology and Infection Research, and Centre for Immunity, Infection and Evolution, School of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK
                [4 ]Wellcome Centre for Molecular Parasitology, Institute for Infection, Immunity and Inflammation, University of Glasgow, Sir Graeme Davies Building, 120 University Place, Glasgow G12 8TA, UK
                [5 ]SynthSys, The Kings Buildings, University of Edinburgh, Edinburgh EH9 3BF, UK
                [6 ]The Edinburgh Protein Production Facility (EPPF), Wellcome Trust Centre for Cell Biology (WTCCB), University of Edinburgh, King's Buildings, Max Born Crescent, Mayfield Road, Edinburgh EH9 3BF, UK
                [7 ]Centre for Immunology and Infection, Department of Biology, University of York YO10 5DD, York, UK
                [8 ]Department of Pathology, Laboratory Medicine, Royal Infirmary of Edinburgh, Edinburgh, UK
                Author notes
                []Corresponding author rick.maizels@
                [∗∗ ]Corresponding author henry.mcsorley@

                These authors contributed equally


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                © 2017 The Author(s)

                This is an open access article under the CC BY license (



                parasite, allergy, asthma, immunomodulation, helminth, il-33


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