Deciphering sex differences in the human immune system
Women face a four-fold higher risk of developing an autoimmune disease compared to men. Sex differences in immune-mediated disorders are well-documented, but have remained poorly understood and are not taken into account in current therapies. To improve treatment of sex-biased autoimmune disorders I believe it will be essential to gain a much deeper understanding of fundamental factors controlling sex differences in the human immune system. The present proposal applies two uniquely informative human model systems to determine the separate roles of sex hormones and sex chromosomes in immune regulation. First we will investigate how the immune system is transformed during female-to-male and male-to-female sex change, utilizing samples collected in a multicenter study that I am coordinating. A combination of broad-scale technologies will be applied to follow dynamics provoked by sex hormone transition in peripheral blood immune cells, autoimmune reactivity, plasma proteins, and gut microbiota. As a complementary model to capture effects mediated by sex chromosomes, we will study mosaic individuals harboring immune cells with both female and male karyotypes in peripheral blood. Single cell transcriptomic analysis will be used to compare these cell populations, thereby revealing the influence of chromosomal sex in an otherwise fixed genetic and hormonal background. These model systems will be combined with population-based studies - taking advantage of new data on sex hormone levels and sex chromosome karyotypes in 500,000 women and men (UK Biobank), which will allow us to determine how these factors ultimately influence the risk of autoimmune disease.  I believe this novel approach will offer groundbreaking insights into the biology of sex differences of human immune systems, thus providing a foundation for development of new treatment strategies for sex-biased autoimmune disorders.