title: AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies.
abstract: APS1/APECED patients are defined by defects in the autoimmune regulator (AIRE) that mediates central T cell tolerance to many self-antigens. AIRE deficiency also affects B cell tolerance, but this is incompletely understood. Here we show that most APS1/APECED patients displayed B cell autoreactivity toward unique sets of approximately 100 self-proteins. Thereby, autoantibodies from 81 patients collectively detected many thousands of human proteins. The loss of B cell tolerance seemingly occurred during antibody affinity maturation, an obligatorily T cell-dependent step. Consistent with this, many APS1/APECED patients harbored extremely high-affinity, neutralizing autoantibodies, particularly against specific cytokines. Such antibodies were biologically active in vitro and in vivo, and those neutralizing type I interferons (IFNs) showed a striking inverse correlation with type I diabetes, not shown by other anti-cytokine antibodies. Thus, naturally occurring human autoantibodies may actively limit disease and be of therapeutic utility.
authors.affiliation: ImmunoQure AG, Königsallee 90, 2012 Düsseldorf, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Meyer
authors.affiliation: Peter Gorer Department of Immunobiology, King's College, London SE19RT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Woodward
authors.affiliation: ImmunoQure AG, Königsallee 90, 2012 Düsseldorf, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Hertel
authors.affiliation: ImmunoQure AG, Königsallee 90, 2012 Düsseldorf, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Vlaicu
authors.affiliation: Peter Gorer Department of Immunobiology, King's College, London SE19RT, UK.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Haque
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
authors.forename: Jaanika
authors.initials: J
authors.lastname: Kärner
authors.affiliation: ImmunoQure Research AG, Wagistrasse 14, 8952 Schlieren, Switzerland.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Macagno
authors.affiliation: ImmunoQure Research AG, Wagistrasse 14, 8952 Schlieren, Switzerland.
authors.forename: Shimobi C
authors.initials: SC
authors.lastname: Onuoha
authors.affiliation: Institute of Computer Science, University of Tartu, Liivi 2, Tartu 50409, Estonia; Quretec Ltd., Ülikooli 6A, Tartu 51003, Estonia.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Fishman
authors.affiliation: Institute of Computer Science, University of Tartu, Liivi 2, Tartu 50409, Estonia; Quretec Ltd., Ülikooli 6A, Tartu 51003, Estonia.
authors.forename: Hedi
authors.initials: H
authors.lastname: Peterson
authors.affiliation: Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
authors.forename: Kaja
authors.initials: K
authors.lastname: Metsküla
authors.affiliation: Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
authors.forename: Raivo
authors.initials: R
authors.lastname: Uibo
authors.affiliation: Clinical Research Institute HUCH Ltd., Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: Kirsi
authors.initials: K
authors.lastname: Jäntti
authors.affiliation: Clinical Research Institute HUCH Ltd., Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Hokynar
authors.affiliation: Department of Clinical Science, University of Bergen, Laboratory Building, 8th floor, 5021 Bergen, Norway.
authors.forename: Anette S B
authors.initials: ASB
authors.lastname: Wolff
authors.affiliation: Clinical Research Institute HUCH Ltd., Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: Kai
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Department of Dermatology, Allergology and Venereology, Institute of Clinical Medicine, University of Helsinki, Skin and Allergy Hospital, Helsinki University Central Hospital, Meilahdentie 2, 00250 Helsinki, Finland.
authors.forename: Annamari
authors.initials: A
authors.lastname: Ranki
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
authors.forename: Pärt
authors.initials: P
authors.lastname: Peterson
authors.affiliation: Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia. Electronic address: kai.kisand@ut.ee.
authors.forename: Kai
authors.initials: K
authors.lastname: Kisand
authors.affiliation: Peter Gorer Department of Immunobiology, King's College, London SE19RT, UK. Electronic address: adrian.hayday@kcl.ac.uk.
authors.forename: Adrian
authors.initials: A
authors.lastname: Hayday
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000915:Antibody Affinity; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D060467:Disease Resistance / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency*; D055815:Young Adult; D000096927:AIRE Protein
chemical_list: D057134:Antibodies, Neutralizing; D001323:Autoantibodies; D016207:Cytokines; D014157:Transcription Factors; D000096927:AIRE Protein