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Cell. 2016 Jul 28;166(3):582-95. doi: 10.1016/j.cell.2016.06.024. Epub 2016 Jul 14.

AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies.

Author information

1
ImmunoQure AG, Königsallee 90, 2012 Düsseldorf, Germany.
2
Peter Gorer Department of Immunobiology, King's College, London SE19RT, UK.
3
Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
4
ImmunoQure Research AG, Wagistrasse 14, 8952 Schlieren, Switzerland.
5
Institute of Computer Science, University of Tartu, Liivi 2, Tartu 50409, Estonia; Quretec Ltd., Ülikooli 6A, Tartu 51003, Estonia.
6
Department of Immunology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia.
7
Clinical Research Institute HUCH Ltd., Haartmaninkatu 8, 00290 Helsinki, Finland.
8
Department of Clinical Science, University of Bergen, Laboratory Building, 8th floor, 5021 Bergen, Norway.
9
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.
10
Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 19, Tartu 50411, Estonia. Electronic address: kai.kisand@ut.ee.
11
Peter Gorer Department of Immunobiology, King's College, London SE19RT, UK. Electronic address: adrian.hayday@kcl.ac.uk.

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.

PMID:
27426947
PMCID:
PMC4967814
DOI:
10.1016/j.cell.2016.06.024
[Indexed for MEDLINE]
Free PMC Article
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