Loss of tolerance precedes triggering and lifelong persistence of pathogenic type I interferon autoantibodies
Sonja Fernbach, Nina K. Mair, Irène A. Abela, Kevin Groen, Roger Kuratli, Marie Lork, Christian W. Thorball, Enos Bernasconi, Paraskevas Filippidis, Karoline Leuzinger, Julia Notter, Andri Rauch, Hans H. Hirsch, Michael Huber, Huldrych F. Günthard, Jacques Fellay, Roger D. Kouyos, Benjamin G. Hale, The Swiss HIV Cohort Study, Irène A. Abela, Karoline Aebi‐Popp, A Anagnostopoulos, Manuel Battegay, Enos Bernasconi, Dominique L. Braun, Heiner C. Bucher, Alexandra Calmy, Matthias Cavassini, Angela Ciuffi, G Dollenmaier, Matthias Egger, Luisa Elzi, Jan Fehr, Jacques Fellay, Hansjakob Furrer, Christoph A. Fux, Huldrych F. Günthard, Anna Hachfeld, D Haerry, Barbara Hasse, Hans H. Hirsch, Matthias Hoffmann, Irène Hösli, Michael Huber, David Jackson‐Perry, Christian R. Kahlert, Laurent Kaiser, Olivia Keiser, Thomas Klimkait, Roger D. Kouyos, Helen Kovari, Katharina Kusejko, Niklaus Daniel Labhardt, Karoline Leuzinger, Begogna Martinez de Tejada, Catja Marzolini, Karin J. Metzner, Nicolas Müller, Johannes Nemeth, Dunja Nicca, Julia Notter, P Paioni, Giuseppe Pantaleo, Matthieu Perreau, Andri Rauch, Luisa Salazar‐Vizcaya, Patrick Schmid, Roberto F. Speck, M Stöckle, Philip Tarr, Alexandra Trkola, Gilles Wandeler, Maja Weisser, Sabine Yerly
Abstract
Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.