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J Immunol. 2018 Aug 1;201(3):874-887. doi: 10.4049/jimmunol.1701318. Epub 2018 Jun 29.

Breakdown of Immune Tolerance in AIRE-Deficient Rats Induces a Severe Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy-like Autoimmune Disease.

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Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM Université de Nantes, 44093 Nantes, France.
Institut de Transplantation Urologie Néphrologie, CHU Nantes, 44093 Nantes, France.
Anatomie et Cytologie Pathologiques, CHU Nantes, 44093 Nantes, France.
Transgenesis Rat Immunophenomic Platform, INSERM 1064 and SFR Francois Bonamy, CNRS UMS3556, 44093 Nantes, France.
Molecular Pathology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu 50411, Estonia; and.
Laboratoire d'Immunologie, CHU Nantes, 44093 Nantes, France.
Centre de Recherche en Transplantation et Immunologie UMR 1064, INSERM Université de Nantes, 44093 Nantes, France;


Autoimmune regulator (AIRE) deficiency in humans induces a life-threatening generalized autoimmune disease called autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), and no curative treatments are available. Several models of AIRE-deficient mice have been generated, and although they have been useful in understanding the role of AIRE in central tolerance, they do not reproduce accurately the APECED symptoms, and thus there is still a need for an animal model displaying APECED-like disease. We assessed, in this study, the potential of the rat as an accurate model for APECED. In this study, we demonstrate that in rat, AIRE is expressed by MHC class II (MCH-II)+ and MHC-II- medullary thymic epithelial cells in thymus and by CD4int conventional dendritic cells in periphery. To our knowledge, we generated the first AIRE-deficient rat model using zinc-finger nucleases and demonstrated that they display several of the key symptoms of APECED disease, including alopecia, skin depigmentation, and nail dystrophy, independently of the genetic background. We observed severe autoimmune lesions in a large spectrum of organs, in particular in the pancreas, and identified several autoantibodies in organs and cytokines such as type I IFNs and IL-17 at levels similar to APECED. Finally, we demonstrated a biased Ab response to IgG1, IgM, and IgA isotypes. Altogether, our data demonstrate that AIRE-deficient rat is a relevant APECED animal model, opening new opportunity to test curative therapeutic treatments.

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