title: Human mannose-binding lectin inhibitor prevents Shiga toxin-induced renal injury.
abstract: Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC HUS) is a worldwide endemic problem, and its pathophysiology is not fully elucidated. Here we tested whether the mannose-binding lectin (MBL2), an initiating factor of lectin complement pathway activation, plays a crucial role in STEC HUS. Using novel human MBL2-expressing mice (MBL2 KI) that lack murine Mbls (MBL2(+/+)Mbl1(-/-)Mbl2(-/-)), a novel STEC HUS model consisted of an intraperitoneal injection with Shiga toxin-2 (Stx-2) with or without anti-MBL2 antibody (3F8, intraperitoneal). Stx-2 induced weight loss, anemia, and thrombocytopenia and increased serum creatinine, free serum hemoglobin, and cystatin C levels, but a significantly decreased glomerular filtration rate compared with control/sham mice. Immunohistochemical staining revealed renal C3d deposition and fibrin deposition in glomeruli in Stx-2-injected mice. Treatment with 3F8 completely inhibited serum MBL2 levels and significantly attenuated Stx-2 induced-renal injury, free serum hemoglobin levels, renal C3d, and fibrin deposition and preserved the glomerular filtration rate. Thus, MBL2 inhibition significantly protected against complement activation and renal injury induced by Stx-2. This novel mouse model can be used to study the role of complement, particularly lectin pathway-mediated complement activation, in Stx-2-induced renal injury.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ozaki
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Ying Siow
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Vasile I
authors.initials: VI
authors.lastname: Pavlov
authors.affiliation: Department of Pediatrics, Cardiovascular Thrombosis Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Bohan
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Cardiovascular Thrombosis Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Boyle
authors.affiliation: Department of Pediatrics, Cardiovascular Thrombosis Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Rafail I
authors.initials: RI
authors.lastname: Kushak
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Clinical Immunology and Tissue Typing Lab, University Hospital of Copenhagen, Rigshospitalet, Denmark.
authors.forename: Mikkel-Ole
authors.initials: MO
authors.lastname: Skjoedt
authors.affiliation: Department of Pediatrics, Cardiovascular Thrombosis Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Eric F
authors.initials: EF
authors.lastname: Grabowski
authors.affiliation: Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Taira
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: gstahl@partners.org.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D003167:Complement Activation / Q000187:drug effects; D015933:Complement C3d / Q000378:metabolism*; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D055879:Gene Knock-In Techniques; D005919:Glomerular Filtration Rate; D006463:Hemolytic-Uremic Syndrome / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007668:Kidney / Q000276:immunology; D008297:Male; D037601:Mannose-Binding Lectin / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022641:Shiga Toxin 2 / Q000276:immunology / Q000633:toxicity*; D054323:Shiga-Toxigenic Escherichia coli / Q000378:metabolism
chemical_list: C419226:3F8 antibody; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007074:Immunoglobulin G; C445619:MBL2 protein, human; D037601:Mannose-Binding Lectin; C445639:Mbl2 protein, mouse; D022641:Shiga Toxin 2; C069858:mannose binding protein A; D015933:Complement C3d
keywords: antibody; complement activation; deposition; fibrin; lectin pathway