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

Cell. 2016 Jul 28;166(3):582-595. doi: 10.1016/j.cell.2016.06.024. Epub 2016 Jul 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Animals
  • Antibodies, Neutralizing / immunology
  • Antibody Affinity*
  • Autoantibodies / immunology*
  • Child
  • Child, Preschool
  • Cytokines / immunology
  • Diabetes Mellitus, Type 1 / immunology
  • Disease Resistance / immunology*
  • Humans
  • Immune Tolerance
  • Mice, Inbred C57BL
  • Middle Aged
  • Polyendocrinopathies, Autoimmune / immunology*
  • T-Lymphocytes / immunology
  • Transcription Factors / deficiency*
  • Young Adult


  • APECED protein
  • Antibodies, Neutralizing
  • Autoantibodies
  • Cytokines
  • Transcription Factors