Translating Sex Differences in Immunity to Improve Health

Biological sex, meaning the differences between males and females caused by differential sex chromosome complement, reproductive tissues, and concentrations of sex steroids, impacts the functioning of the immune system. Sex differences in immune function can occur as a result of differential expression of X-linked and autosomal genes due to epigenetic modifications as well as changes in sex steroid receptor signaling inside of immune cells over the life course. Sex differences in immune function are documented across diverse innate and adaptive cell types, signaling pathways, and responses both at a resting state as well as in the context of diverse diseases, ranging from autoimmune diseases and allergy-induced asthma to microbial infection and cancers.

These sex differences in immunity not only impact the pathogenesis of diverse diseases, but the responses to immunomodulatory treatments, including vaccines, monoclonal antibody therapies, and immune checkpoint inhibitors. Understanding how these sex differences in immunity occur, the breadth of their impact, and how to utilize these data to inform clinical trials and optimization of treatments requires concerted efforts and an opportunity to bring basic scientists, data scientists, clinician scientists, and epidemiologists together to work through problems and develop consensus about sex differences in immunity.

Although sex differences in immune function have been documented for decades, the COVID-19 pandemic considerably raised awareness about the implications of sex differences in immunity to viruses. In fact, prior to the pandemic caused by SARS-CoV- 2, male-biased severe outcomes from viral infections had been reported for seasonal influenza viruses, SARS and MERS viruses, hemorrhagic fever viruses, hepatitis B and C viruses, and herpes viruses. In many of these cases, the sex differences are age dependent and are associated with reduced antiviral immunity and control of virus replication.

For other viruses, including pandemic influenza viruses and HIV, females suffer worse outcomes than males which is associated with the exuberant immune responses mounted to control infection (i.e., immunopathology). We use this to highlight that little is known about sex differences in the immunological balance between resistance to disease and tolerance of disease. In addition to viruses, sex differences are observed in response to bacteria (e.g., TB, S. aureus), parasites (e.g., Plasmodium spp), fungi, allergens, and self- antigens (i.e., autoimmune diseases). One of the most staggering statistics pertaining to sex-based differences is that 80% of all autoimmune disease patients are women and we still do not fully understand the extent of how genetic, hormonal, and even microbiome differences develop between the sexes either over the life course or through evolutionary processes. Such knowledge will aid in the translation of sex differences in immunity to improve health for all, but in particular women.