title: A recombinant fusion protein derived from dog hookworm inhibits autoantibody-induced dermal-epidermal separation ex vivo.
abstract: The proteins secreted by parasitic nematodes are evolutionarily optimized molecules with unique capabilities of suppressing the immune response of the host organism. Neutrophil inhibitory factor (NIF), which is secreted by the dog hookworm Ancylostoma caninum, binds to the β2 integrin CD11b/CD18, which is expressed on human neutrophils, eosinophils, monocytes and macrophages and inhibits neutrophil-dependent lung injury and neutrophil invasion of ischaemic brain tissue. Neutrophils are key players in the pathogenesis of subepidermal autoimmune blistering diseases (sAIBDs), and their pathogenic activities are crucially dependent on β2 integrin functionality. Based on the template of single-stranded, dimerizing antibody derivatives, which are already used in cancer treatment, we designed a novel biologic, NIF-IGHE-CH4, comprising NIF and the dimerizing but otherwise inert constant heavy subdomain 4 (CH4) of human IgE (IGHE). This molecule was evaluated in a variety of in vitro assays, demonstrating its ability to inhibit pathogenically relevant neutrophil functions such as migration, adhesion and spreading, and release of reactive oxygen species. Finally, we confirmed that NIF-IGHE-CH4 inhibits blister formation in an ex vivo assay of sAIBD. These results suggest that NIF-IGHE-CH4 is a novel potential anti-inflammatory drug for the treatment of neutrophil-mediated diseases such as sAIBDs. This study promotes the drugs from bugs concept and encourages further research and development focused on turning parasite proteins into useful anti-inflammatory biologics.
authors.affiliation: Department of Dermatology Allergology and Venereology, University of Lübeck, Lübeck, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Kemmer
authors.affiliation: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Department of Dermatology Allergology and Venereology, University of Lübeck, Lübeck, Germany.
authors.forename: Aida
authors.initials: A
authors.lastname: Abadpour
authors.affiliation: Biochemical Immunology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel (Sülfeld), Germany.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Dermatology Allergology and Venereology, University of Lübeck, Lübeck, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Mitschker
authors.affiliation: Institute for Medical Microbiology and Hygiene, University of Lübeck, Lübeck, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Roth
authors.affiliation: Department of Dermatology Allergology and Venereology, University of Lübeck, Lübeck, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kauderer
authors.affiliation: Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.affiliation: Institute of Chemistry, University of Lübeck, Lübeck, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Seeger
authors.affiliation: Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.affiliation: Department of Dermatology Allergology and Venereology, University of Lübeck, Lübeck, Germany.|Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Department of Dermatology Allergology and Venereology, University of Lübeck, Lübeck, Germany.|Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany.
authors.forename: Andreas
authors.identifier: http://orcid.org/0000-0002-7674-1804
authors.initials: A
authors.lastname: Recke
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006023:Glycoproteins; D015801:Helminth Proteins; D006801:Humans; D008565:Membrane Proteins; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D012872:Skin Diseases, Vesiculobullous / Q000188:drug therapy*
chemical_list: D006023:Glycoproteins; D015801:Helminth Proteins; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; C086581:NIF protein, Ancylostoma caninum
keywords: autoimmune blistering disease; beta-2 integrin; neutrophil inhibition; neutrophils; parasite proteins