Our project investigates the impact of sex hormones and genetic factors on immune responses, structured into three work packages (WPs).
WP1 Achievements: Sex Hormones and Immunity
We have completed a study on immune system adaptations during gender-affirming testosterone treatment in transgender men. We report that sex hormones modulate a cross-regulation axis between type-I interferon (IFN-I) and TNFa. Key observations include a reduced frequency of plasmacytoid dendritic cells (pDCs) and attenuated IFN-I responses in pDCs and monocytes, paralleled by an enhanced pro-inflammatory response in monocytes. Our results provide insights into the dynamic recalibration of the immune system by sex hormones, with relevance for individuals undergoing gender-affirming hormone therapy and broad implications for sex differences in immune-related diseases. The finding that testosterone modulates the type I IFN system insight is especially critical given the known overactivation of the type I IFN system in autoimmune diseases predominantly affecting women, such as systemic lupus erythematosus (SLE), coupled with the increased risk of severe outcomes from COVID-19 in males.
WP2 Achievements: Genetic Factors and Immunity
In WP2, we focus on individuals with sex chromosome aberrations to understand the genetic influence on immunity. We are using two main approaches: 1) comparing immune functions between groups of individuals with different karyotypes (46XX, 46XY, 45X, 47XXY), and 2) comparing peripheral blood immune cells with different karyotypes within mosaic individuals (46XX/46XY, 46XX/45X). Our initial efforts have focused on developing methodologies to classify cells by karyotype using single-cell RNA sequencing data, and we now have a feasible approach to proceed with. Additionally, we have established protocols for evaluating immune responses through in vitro stimulation assays in healthy individuals. We have started collecting samples from immune stimulation experiments in 46XX women and 46XY men that will be included in the study comparing functional immune responses between groups of individuals with different sex chromosome karyotypes. We have also started collecting single-cell transcriptomics data from individuals with mosaicism.
WP3 Achievements: Population-level Analysis of Sex Differences in Autoimmunity
The third phase of our project will investigate the effects of sex hormones and genetics on immunity at the population level. We will perform autoantibody profiling in 1000 healthy volunteers the Milieu Interieur cohort to assess how autoimmune reactivity differs between women and men and in relation to sex hormone variation.
In conclusion, our project has made substantial progress toward the project aim of elucidating the interplay between sex hormones, genetic factors, and immune responses.
