Impaired Aire-dependent IFN signaling in the thymus precedes the protective autoantibodies to IFNα
Recent studies have highlighted the role of the thymus in maintaining immune tolerance to type 1 interferons (T1 IFNs). Individuals with thymic abnormalities, such as autoimmune regulator (AIRE) gene mutations, frequently develop neutralizing autoantibodies to interferon-alpha (IFNα). Unlike mice, Aire-deficient rats develop robust autoantibodies to IFNα. Using this rat model, we show that Aire regulates the thymic expression of interferon-stimulated genes (ISGs), which occurs before developing anti-IFNα autoantibodies. In the periphery, we observed a widespread downregulation of ISGs across immune cells and reduced activation of natural killer (NK) cells. Furthermore, the presence of anti-IFNα autoantibodies correlated with reduced peripheral tissue inflammation, suggesting their role in dampening T1 IFN signaling and minimizing tissue infiltration. Our findings reveal that Aire-mediated regulation of thymic T1 IFN signaling is linked to the production of protective anti-IFNα autoantibodies, which inversely correlate with autoimmune pathology in peripheral tissues.
Authors
- Martti Laan (ORCID: https://orcid.org/0000-0002-0448-8627)
- Maksym Zarodniuk (ORCID: https://orcid.org/0000-0002-3953-315X)
- Romain Humeau
- Liis Haljasmägi (ORCID: https://orcid.org/0000-0001-7162-9808)
- Carole Guillonneau (ORCID: https://orcid.org/0000-0002-7195-0631)
- Marine Besnard (ORCID: https://orcid.org/0000-0002-3009-5528)
- Rudolf Bichele
- Ahto Salumets (ORCID: https://orcid.org/0000-0002-1528-3715)
- Uku Haljasorg (ORCID: https://orcid.org/0000-0002-1541-6020)
- Pärt Peterson (ORCID: https://orcid.org/0000-0001-6755-791X)
- Liina Tserel
- Eliisa Kekäläinen (ORCID: https://orcid.org/0000-0001-6045-108X)
- Kai Kisand (ORCID: https://orcid.org/0000-0002-5426-4648)
- Artur Stoljar
- Merili Peltser
- Elise Helene Armulik (ORCID: https://orcid.org/0009-0009-1379-1183)
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Helsinki (FI)
- Inserm (FR)
- Center for Research in Transplantation and Translational Immunology
- University of Tartu (EE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-04-30
- DOI
- https://doi.org/10.1084/jem.20241403
- Citations
- 3
- Primary Topic
- Adrenal Hormones and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.88
Funders
- Agence Nationale de la Recherche
- Eesti Teadusagentuur
- European Regional Development Fund