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

Steffen Meyer, Martin Woodward, Christina Hertel, Philip Vlaicu, Yasmin Haque, Jaanika Kärner, Annalisa Macagno, Shimobi C. Onuoha, Dmytro Fishman, Hedi Peterson, Kaja Metsküla, Raivo Uibo, Kirsi Jäntti, Kati Hokynar, Anette S. B. Wolff, Antonella Meloni, Nicolas Kluger, Eystein S. Husebye, Katarina Trebusak Podkrajsek, Tadej BattelinoNina Bratanic, Aleksandr Peet, Kai Krohn, Annamari Ranki, Pärt Peterson, Kai Kisand*, Adrian Hayday

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

200 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)582-595
Number of pages14
JournalCell
Volume166
Issue number3
Early online date14 Jul 2016
DOIs
Publication statusPublished - 28 Jul 2016

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