title: Loss of immune tolerance to IL-2 in type 1 diabetes.
abstract: Type 1 diabetes (T1D) is characterized by a chronic, progressive autoimmune attack against pancreas-specific antigens, effecting the destruction of insulin-producing β-cells. Here we show interleukin-2 (IL-2) is a non-pancreatic autoimmune target in T1D. Anti-IL-2 autoantibodies, as well as T cells specific for a single orthologous epitope of IL-2, are present in the peripheral blood of non-obese diabetic (NOD) mice and patients with T1D. In NOD mice, the generation of anti-IL-2 autoantibodies is genetically determined and their titre increases with age and disease onset. In T1D patients, circulating IgG memory B cells specific for IL-2 or insulin are present at similar frequencies. Anti-IL-2 autoantibodies cloned from T1D patients demonstrate clonality, a high degree of somatic hypermutation and nanomolar affinities, indicating a germinal centre origin and underscoring the synergy between cognate autoreactive T and B cells leading to defective immune tolerance.
authors.affiliation: Sorbonne Universités, Pierre and Marie Curie University Paris 06, Paris 75005, France.|Centre National de la Recherche Scientifique, UMR 7211, Paris 75013, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U 959, Immunology- Immunopathology-Immunotherapy (I3), Paris 75013, France.|Institut Curie, PSL Research University, INSERM U932, F-75005 Paris, France.|SiRIC TransImm Translational Immunotherapy Team, Translational Research Department, Research Center, PSL Research University, Institut Curie, Paris F-75005, France.|Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris F-75005, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Pérol
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: John M
authors.initials: JM
authors.lastname: Lindner
authors.affiliation: Institut Curie, PSL Research University, INSERM U932, F-75005 Paris, France.|SiRIC TransImm Translational Immunotherapy Team, Translational Research Department, Research Center, PSL Research University, Institut Curie, Paris F-75005, France.|Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris F-75005, France.
authors.forename: Pamela
authors.initials: P
authors.lastname: Caudana
authors.affiliation: Institut Curie, PSL Research University, INSERM U932, F-75005 Paris, France.|SiRIC TransImm Translational Immunotherapy Team, Translational Research Department, Research Center, PSL Research University, Institut Curie, Paris F-75005, France.|Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris F-75005, France.
authors.forename: Nicolas Gonzalo
authors.initials: NG
authors.lastname: Nunez
authors.affiliation: Sorbonne Universités, Pierre and Marie Curie University Paris 06, Paris 75005, France.|Centre National de la Recherche Scientifique, UMR 7211, Paris 75013, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U 959, Immunology- Immunopathology-Immunotherapy (I3), Paris 75013, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Baeyens
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Valle
authors.affiliation: Institut Curie, PSL Research University, INSERM U932, F-75005 Paris, France.|SiRIC TransImm Translational Immunotherapy Team, Translational Research Department, Research Center, PSL Research University, Institut Curie, Paris F-75005, France.|Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris F-75005, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Sedlik
authors.affiliation: SiRIC TransImm Translational Immunotherapy Team, Translational Research Department, Research Center, PSL Research University, Institut Curie, Paris F-75005, France.|Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris F-75005, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Loirat
authors.affiliation: INSERM, U905, Rouen 76183, France.|Normandie Univ. IRIB, Rouen 76183, France.|Rouen University Hospital, Laboratory of Immunology, Rouen 76183, France.
authors.forename: Olivier
authors.identifier: 0000-0002-7591-307X
authors.initials: O
authors.lastname: Boyer
authors.affiliation: Service de Neurologie, Groupe Hospitalier Henri Mondor, AP-HP, Créteil F-94010, France.|EA 4391, Université Paris Est, Créteil F-94010, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Créange
authors.affiliation: Université Paris-Est Créteil, Créteil F-94010, France.|INSERM U 955, Institut Mondor de Recherche Biomédicale (IMRB), Créteil F-94010, France.|AP-HP, Groupe Hospitalier Henri-Mondor Albert-Chenevier, CIC-BT-504, Créteil F-94010, France.
authors.forename: José Laurent
authors.initials: JL
authors.lastname: Cohen
authors.affiliation: Institut Pasteur, CNRS URA 2578, Département Biologie du développement et cellules souches, Paris 75015, France.
authors.forename: Ute Christine
authors.initials: UC
authors.lastname: Rogner
authors.affiliation: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine. University of Calgary, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Martine
authors.initials: M
authors.lastname: Marchant
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Xavier Charles
authors.initials: XC
authors.lastname: Leber
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Meike
authors.initials: M
authors.lastname: Scharenberg
authors.affiliation: INSERM, U1016, Cochin Institute, DeAR Lab, Paris 75014, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Diabétologie, Paris 75014, France.|Paris Descartes University, Sorbonne Paris Cité, Faculté de Médecine, Paris 75270, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gagnerault
authors.affiliation: INSERM, U1016, Cochin Institute, DeAR Lab, Paris 75014, France.|Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Diabétologie, Paris 75014, France.|Paris Descartes University, Sorbonne Paris Cité, Faculté de Médecine, Paris 75270, France.
authors.forename: Roberto
authors.identifier: 0000-0002-9846-8861
authors.initials: R
authors.lastname: Mallone
authors.affiliation: Diabetes Research Institute (DRI), IRCCS San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Battaglia
authors.affiliation: Julia McFarlane Diabetes Research Centre and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases, Cumming School of Medicine. University of Calgary, Calgary, Alberta, Canada T2N 4N1.|Institut D'Investigacions Biomediques August Pi i Sunyer, Barcelona 08036, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
authors.affiliation: Department of Medicine Faculty, Université Pierre et Marie Curie-Paris 6, Paris 75005, France.|Department of Endocrinology, Nutrition and Diabetes, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière-Charles Foix Hospital, Paris 75013, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Hartemann
authors.affiliation: Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Traggiai
authors.affiliation: Sorbonne Universités, Pierre and Marie Curie University Paris 06, Paris 75005, France.|Centre National de la Recherche Scientifique, UMR 7211, Paris 75013, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), U 959, Immunology- Immunopathology-Immunotherapy (I3), Paris 75013, France.|Institut Curie, PSL Research University, INSERM U932, F-75005 Paris, France.|SiRIC TransImm Translational Immunotherapy Team, Translational Research Department, Research Center, PSL Research University, Institut Curie, Paris F-75005, France.|Centre d'Investigation Clinique Biothérapie CICBT 1428, Institut Curie, Paris F-75005, France.
authors.forename: Eliane
authors.initials: E
authors.lastname: Piaggio
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008875:Middle Aged; D010179:Pancreas / Q000276:immunology; D010455:Peptides / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D000939:Epitopes; C508594:IL2 protein, human; D007074:Immunoglobulin G; D007376:Interleukin-2; D010455:Peptides