Breakdown of immune tolerance in AIRE-deficient rats induces a severe APECED-like auto-immune disease

AIRE-deficiency in human induces a life-threatening generalized autoimmune disease called 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 here the potential of the rat as an accurate model for APECED. We demonstrate here that in rat,AIRE is expressed by MHCII+ and MHCII- mTECs in thymus, and CD4int conventional DCs in periphery. We generated the first AIRE-deficient rat model using zinc finger nucleases and demonstrated that they display most of the key symptoms of APECED disease independently of the genetic background including alopecia, skin depigmentation and nail-dystrophy. We observed severe autoimmune lesions in a large spectrum of organs, in particular in the pancreas, and identified several auto-antibodies to organs and cytokines such as type I IFNs at levels similar to APECED. Finally, we demonstrated a biased antibody response to IgG1, IgM and IgA isotypes and an altered primary T cell response to self and non-self, but not secondary response. Altogether, we demonstrate that AIRE-deficient rat is a relevant APECED animal model opening new opportunity to test curative therapeutic treatments.