AIRE-deficient patients harbor unique high-affinity disease-ameliorating autoantibodies
journal contributionposted on 07.09.2020, 11:19 by 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 SB Wolff, APECED patient collaborative, Kai Krohn, Annamari Ranki, Pärt Peterson, Kai Kisand, Adrian Hayday
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.
AdolescentAdultAgedAnimalsAntibodies, NeutralizingAntibody AffinityAutoantibodiesChildChild, PreschoolCytokinesDiabetes Mellitus, Type 1Disease ResistanceHumansImmune ToleranceMice, Inbred C57BLMiddle AgedPolyendocrinopathies, AutoimmuneT-LymphocytesTranscription FactorsYoung AdultAPECED patient collaborativeHayday FC001093Developmental Biology06 Biological Sciences11 Medical and Health Sciences