AIRE deficiency, from preclinical models to human APECED disease

Abstract

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare life-threatening autoimmune disease that attacks multiple organs and has its onset in childhood. It is an inherited condition caused by a variety of mutations in the autoimmune regulator (AIRE) gene that encodes a protein whose function has been uncovered by the generation and study of Aire-KO mice. These provided invaluable insights into the link between AIRE expression in medullary thymic epithelial cells (mTECs), and the broad spectrum of self-antigens that these cells express and present to the developing thymocytes. However, these murine models poorly recapitulate all phenotypic aspects of human APECED. Unlike Aire-KO mice, the recently generated Aire-KO rat model presents visual features, organ lymphocytic infiltrations and production of autoantibodies that resemble those observed in APECED patients, making the rat model a main research asset. In addition, ex vivo models of AIRE-dependent self-antigen expression in primary mTECs have been successfully set up. Thymus organoids based on pluripotent stem cell-derived TECs from APECED patients are also emerging, and constitute a promising tool to engineer AIRE-corrected mTECs and restore the generation of regulatory T cells. Eventually, these new models will undoubtedly lead to main advances in the identification and assessment of specific and efficient new therapeutic strategies aiming to restore immunological tolerance in APECED patients.

Anti-CD45RC antibody immunotherapy prevents and treats experimental autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome

“…Targeted immunotherapies have opened a new era of opportunities to treat rare and multiorgan autoimmune diseases that are more challenging to treat than more frequent autoimmune diseases affecting wider patient populations. Typically, the study of rare diseases can be difficult because of the lack of animal models, the paucity of patients, and the difficulty of executing powered clinical trials ( 17 ). Although APECED is a rare disease, its prevalence can reach higher proportions in some populations, such as 1:25,000 in Finns and 1:9000 in Iranian Jews ( 28 , 29 ), and the recent description of dominant monoallelic mutations associated with a later onset of the disease and a milder phenotype suggests that disease-causing AIRE mutation is underestimated ( 30 ).…”

“…Despite the insights gained from these mouse models into the etiology and pathology of APECED, substantial phenotypic and clinical differences exist between Aire-deficient mice and human APECED patients (17). We, several years ago, developed a model of Aire -/rats that ultimately exhibit manifestations resembling the ones seen in APECED patients including nephritis, pneumonitis and pancreatic failure (17)(18)(19). They also harbor visible manifestations, such as alopecia, vitiligo and nail dystrophy, which could be very useful for facile clinical follow-up during preclinical studies.…”

“…Despite the insights gained from these mouse models into the etiology and pathology of APECED, substantial phenotypic and clinical differences exist between AIRE-deficient mice and human APECED patients ( 17 ). Several years ago, we developed a model of Aire –/– rats that ultimately exhibit manifestations resembling the ones seen in APECED patients, including nephritis, pneumonitis, and pancreatic failure ( 17 – 19 ).…”

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

“…Of note, experimental transfer of autoantibody-containing AIRE-deficient serum in mice is not sufficient to promote autoimmunity ( 41 , 42 ). Serum transfer experiments in the recently developed AIRE-deficient rat model, which harbors a broader spectrum of autoantibodies relative to AIRE-deficient mice, may help further elucidate the potential direct role of autoantibodies in autoimmune tissue destruction ( 61 , 62 ).…”

The AIRE G228W mutation disturbs the interaction of AIRE with its partner molecule SIRT1

“…The human autoimmune regulator (AIRE) gene located at chromosome 21q22.3 is 11.9 kb long, spans 14 exons, and encodes an mRNA with 1635 nucleotides, which in turn encodes a 545 aminoacid protein (Aaltonen et al, 1994;Nagamine et al, 1997;Blechschmidt et al, 1999). Nearly 145 mutations have been found along the AIRE gene, from single-nucleotide mutations to large deletions (Wolff and Oftedal, 2019;Besnard et al, 2021; Human Gene Mutation Database available at https://www.hgmd.cf.ac.uk/ac/). Mutations in the AIRE gene are related to polyendocrinopathy autoimmune-candidiasis-ectodermal dystrophy (APECED) (Finnish-German APECED Consortium 1997; Nagamine et al, 1997), also known as polyglandular autoimmune syndrome type 1 (APS1) (OMIM entry # 240300).…”