ESPE Yearbook of Paediatric Endocrinology

Brief summary: This study further explores the sex differences in autoimmune regulation and the control of normal inflammatory responses, and also helps us understand why there are sex differences in the aetiology of autoimmune diseases such as systemic lupus erythematosus (SLE). It demonstrates the changes that occur in cisgender pubertal development on the T regulatory cell (Treg), B cell and monocyte population, and using samples from transgender adolescents undergoing GnRHa then GAH treatment, how certain regulatory genes appear to be under the control of both sex hormones and sex chromosomes following observiations of significant changes in gene expression with transgender hormonal interventions.

The authors identified key sex differences in Treg phenotype and function between healthy individuals, which might explain differences in autoimmune disease susceptibilities and the response to infection. Specifically, they found that the global immune profile was altered by sex, with circulating Tregs more numerous and suppressive in young post-pubertal cisgender men compared with cisgender women. Tregs had a transcriptomic profile which differed between young cisgender men and cisgender women, and this was associated with increased secondary messenger signalling in cisgender men. Naturally secreted sex hormones pre-and post-puberty altered the Treg frequency and transcriptomic functional profile between cisgender men and women, and this finding was further explored in postpubertal transgender adolescents undergoing GAH therapy. The information reported in the study contributes to the understanding of immunopathological mechanisms of sexually dimorphic autoimmune disease development and contributes to the basic understanding of immunology by sex and gender. As observed in cisgender men, transgender men had increased Treg frequencies following GnRHa treatment and early-stage gender-affirming testosterone administration. Sex differences in Treg frequencies in pre-pubertal children were similar to those seen post-puberty. Treg cells in young cisgender men were more suppressive than those in transgender men, cisgender and transgender women, suggesting that both sex hormones and sex chromosomes play a role in driving the increased suppressive function of Tregs noted in cisgender men. The study identified multiple novel genes that could be associated with Treg function by sex. T-responder (Tresp) cells could also be important for the inflammatory balance between cisgender men and women, but this would require additional phenotype and functional analyses. The increased suppressive capacity of Treg cells in cisgender men could also be due to increased proliferation of Tresp cells in cisgender women. The information gathered helps to begin to understand the mechanistic pathogenesis of autoimmune disease and the bias towards cisgender women.