Functional Genomics of the Infant Human Thymus: AIRE and Minipuberty
Sexual dimorphism in the immune system is well documented in humans and it encompasses sex differences in responses to self and foreign antigens. Indeed, women usually mount stronger immune responses to infections and vaccination but have higher susceptibility to autoimmune diseases than men (Klein and Flanagan 2016). Regarding autoimmune diseases, it is striking that 80% of autoimmune patients are women (Rubtsova et al. 2015). Autoimmunity results from a tolerance breakdown and essentially involves the thymus, the site of T cell selection (Cheng and Anderson 2018). T cell selection depends on the ectopic thymic transcription of thousands of genes coding for tissue-specific antigens, which is induced by the autoimmune regulator gene AIRE (Passos et al. 2018; Perniola 2018). In spite of our incomplete knowledge on the biological processes responsible for autoimmunity, it is reasonable to assume that sex hormones impact the genomic mechanisms governing AIRE functions. An important experimental evidence supporting this assumption came from the work of Dumont-Lagacé et al. (2015), who showed in a murine model that sex hormones have pervasive effects on thymic epithelial cells (TEC)—antigen presenting cells that regulate T cell repertoire and tolerance—and that androgens have a greater impact on TEC transcriptome than estrogens. In this study, the authors observed that sex steroids repressed the expression of tissue-restricted antigens but did not alter the expression of Aire. Just after this work, Dragin et al. (2016) demonstrated that estrogen mediates the downregulation of AIRE in human pubescent and adult thymic tissues, thus indicating that the reduced expression of AIRE protein in women may be related to autoimmunity susceptibility. However, this study did not cover infants along the first 6 months of age, i.e. during minipuberty (Kuiri-Hänninen et al. 2014), a period when sex hormones conceivably act on thymic tissue.
Financial Support This work was funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) research grants 2015/22308-2 (CAM-F) and 2014/50489-9 (MC-S); and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant 307626/2014-8 (CAM-F).