O papel modulador do gene AIRE - capes

MANUSCRITOcells (Sospedra et al., 1998; Bruno et al., 2002; Kyewski and Derbinski,2004). While PGE was well characterized in mTECs by the authors abovecited and in intact thymus by our group (Sousa Cardoso et al., 2006;Magalhães et al., 2006), their detailed molecular control requires furtherexploration.A gene identified and cloned in 1997 was termed AIRE (autoimmuneregulator) due to their association with autoimmune polyendocrinopathycandidiasisectodermal dystrophy (APECED) syndrome, a humanautoimmune disease, (Finnish-German APECED Consortium, 1997;Nagamine et al., 1997). Studies in mice have permitted an extensivemechanistic dissection of how Aire operates. It was found that Aire isexpressed primarily in lymphoid organs, especially the thymus. Within thethymus it is expressed mostly by medullary epithelial cells (MECs) stronglyby mTECs but also although at much lower levels, by dendritic cells(Anderson et al., 2002; Anderson et al., 2005).Identifying Aire expression in MECs was intriguing because ofsuggestions that this cell-type is involved in the negative selection of selfreactivethymocytes (Kishimoto and Sprent, 1997) and because of thecoincident emergence of data establishing that transcripts encoding PTAsare ectopically expressed specifically by MECs (Kyewski and Klein, 2006).These evidences allowed the formulation the hypothesis that Aireregulates the thymic transcription of PTA genes and thus thymocytetolerization and therefore autoimmune reactions.The Aire-knockout mice harbored a normal immune system but featuredmulti-organ autoimmunity, as indicated by both inflammatory infiltrates and206