The roles of genetics, hormones, and gender in sexually dimorphic immune response

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ABSTRACT Sex and gender contribute to the immune system and how we as humans respond to foreign infections. Males traditionally have an elevated risk of hospitalizations due to infections from birth to old age. Females, however, have a more protective immune system, yet have an elevated risk of autoimmunity. Thus, the balance between fighting infections and limiting immune response is stratified. Animal models have allowed us to largely tease out the role of sex chromosomes and hormones (such as estrogen/testosterone), but they lend little insight into the role of human gender on the immune response. Disparities between trans- and cis-gender women are observed in multiple inflammatory and immune phenotypes, from HIV risk to rheumatological conditions. As gender is a non-binary spectrum, many precision medicine tools can be applied to tease out individuals’ immune system modulators focused on individual assessments of sex chromosomes, sex hormones, and environmental factors. To do this, we have compiled a multiple PI team that brings strengths from epigenetics/epidemiology (Dr. Triche), infectious disease modeling (Dr. Krawczyk), and sex chromosome/hormone genetics (Dr. Prokop). We highlight in this work how the histone methylation regulator chromosome pair, KDM5C (chrX) and KDM5D (chrY), results in an immune modulation through genome-wide epigenetic alteration. We have developed three complementary aims to build an integrated model of KDM5C/KDM5D influence on individuals’ immune responses. Aim1) Genetics of KDM5C hematopoiesis conditional knockout alteration at the cellular resolution of the immune system following a chronic viral infection, allowing us to determine cell types and global epigenetic alterations regulated by the pathway. Aim2) Precision insights for KDM5C/KDM5D of ~20,000 human blood samples following various immune challenges and the separation of hormone and sex chromosome using the four-core genotypes rodent model blood single-cell data generation. Aim3) Integrating our knowledge to individuals for human variants, gene regulation, environmental modulation, and phenotypic associations for KDM5C/KDM5D. The combination of the three aims represents a precision medicine approach, allowing us insights into the cells and pathways impacted by the sex chromosome genes during infection (Aim1), deconvolution of how hormones and sex chromosomes synergistically contribute to immune cells (Aim2), defining the broad infections and signatures that modulate the genes (Aim2), and integrating this knowledge to be applied to any individual in a non-binary approach (Aim3). As gender can never be binned into groups, with an undefined spectrum of individuals within, we lay forth a novel, innovative way for thinking about how sex and gender both contribute to immune systems without the need for defining gender but allowing for individualized assessments.