Sex differences are observed across the spectrum of human disease, with the most dramatic differences seen for cancer (male predominance) and autoimmunity (female predominance). Variation in immune activity, disease severity, and clinical outcomes, have been observed for viral infections, virally associated cancers, and autoimmune conditions suggesting fundamental differences in immune regulation by biological sex. Sex steroid hormones play an important role in immune function, impacting host susceptibility to infections, autoimmunity, and cancer. Estradiol enhances cell-mediated and humoral immune responses whereas androgens may suppress immune cell activity, reduce pro-inflammatory responses, and inhibit antiviral cytokines. These hormonal differences may also contribute chronic stress responses and epigenetic aging.
We propose to leverage the extensive data on circulating sex hormones (estradiol, testosterone, and sex hormone binding globulin [SHBG]), antibodies to infections, data on infections and autoimmune diseases from health records lab values, DNA methylation data, and mortality records from long-term follow-up of the UK Biobank. We will examine associations between sex hormone levels and the outcomes of 1) antibody response to viral infections (EBV, HPV, HBV, HCV, and HHV), 2) HPV-associated disease (anal and cervical pre-cancerous lesions), 3) autoimmune diseases (multiple sclerosis, lupus, inflammatory bowel disease, and rheumatoid arthritis), mortality (all-cause and cause-specific). Further we will examine whether the association between sex hormone levels and mortality is mediated by epigenetic aging and allostatic load. We will examine these aims in males and females, separately.
The proposed research will contribute to a better understanding of the role of sex steroid hormones in the development of infections, autoimmunity, chronic stress, biological aging, and mortality, leading to a new understanding of mechanisms of action.