title: IgA1 Protease Treatment Reverses Mesangial Deposits and Hematuria in a Model of IgA Nephropathy.
abstract: IgA nephropathy (IgAN), characterized by mesangial IgA1 deposits, is a leading cause of renal failure worldwide. IgAN pathogenesis involves circulating hypogalactosylated IgA1 complexed with soluble IgA Fc receptor I (sCD89) and/or anti-hypogalactosylated-IgA1 autoantibodies, but no specific treatment is available for IgAN. The absence of IgA1 and CD89 homologs in the mouse has precluded in vivo proof-of-concept studies of specific therapies targeting IgA1. However, the α1KI‑CD89Tg mouse model of IgAN, which expresses human IgA1 and human CD89, allows in vivo testing of recombinant IgA1 protease (IgA1‑P), a bacterial protein that selectively cleaves human IgA1. Mice injected with IgA1‑P (1-10 mg/kg) had Fc fragments of IgA1 in both serum and urine, associated with a decrease in IgA1-sCD89 complexes. Levels of mesangial IgA1 deposits and the binding partners of these deposits (sCD89, transferrin receptor, and transglutaminase 2) decreased markedly 1 week after treatment, as did the levels of C3 deposition, CD11b(+) infiltrating cells, and fibronectin. Antiprotease antibodies did not significantly alter IgA1‑P activity. Moreover, hematuria consistently decreased after treatment. In conclusion, IgA1‑P strongly diminishes human IgA1 mesangial deposits and reduces inflammation, fibrosis, and hematuria in a mouse IgAN model, and therefore may be a plausible treatment for patients with IgAN.
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Sebastian M
authors: SM
authors: Lechner
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Lilia
authors: L
authors: Abbad
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Erwan
authors: E
authors: Boedec
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Christina
authors: C
authors: Papista
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Marie-Bénédicte
authors: MB
authors: Le Stang
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Christelle
authors: C
authors: Moal
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Julien
authors: J
authors: Maillard
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Agnès
authors: A
authors: Jamin
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France;
authors: Julie
authors: J
authors: Bex-Coudrat
authors: Shire, Bioprocess Development and Discovery Biology and Translational Research, Lexington, Massachusetts; and.
authors: Yong
authors: Y
authors: Wang
authors: Shire, Bioprocess Development and Discovery Biology and Translational Research, Lexington, Massachusetts; and.
authors: Aiqun
authors: A
authors: Li
authors: Shire, Bioprocess Development and Discovery Biology and Translational Research, Lexington, Massachusetts; and.
authors: Paolo G V
authors: PG
authors: Martini
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France; Immunology Department, Bichat Hospital, Paris Public Assistance Hospitals, Department of Hospital and University (DHU) Fire, Paris, France renato.monteiro@inserm.fr laureline.berthelot@inserm.fr.
authors: Renato C
authors: RC
authors: Monteiro
authors: National French Institute of Health and Medical Research (INSERM) Unit 1149, Center of Research on Inflammation, Paris, France; Laboratory of Inflamex Excellency, Faculty of Medicine, Xavier Bichat Site, Paris, France; Paris Diderot University, Sorbonne Paris Cité, Paris, France; National French Center of Scientific Research (CNRS) ERL8252, Paris, France; renato.monteiro@inserm.fr laureline.berthelot@inserm.fr.
authors: Laureline
authors: L
authors: Berthelot
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000378:metabolism*; D005922:Glomerulonephritis, IGA / Q000188:drug therapy*; D006417:Hematuria / Q000188:drug therapy*; D007070:Immunoglobulin A / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D012697:Serine Endopeptidases / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D007070:Immunoglobulin A; D012697:Serine Endopeptidases; C021433:IgA-specific serine endopeptidase
keywords: IgA nephropathy; glomerulonephritis; immune complexes; immunology; pathology