Sex Differences in Immunity

Abstract

Strong epidemiological evidence now exists that sex is an important biologic variable in immunity. Recent studies, for example, have revealed that sex differences are associated with the severity of symptoms and mortality due to coronavirus disease 2019 (COVID-19). Despite this evidence, much remains to be learned about the mechanisms underlying associations between sex differences and immune-mediated conditions. A growing body of experimental data has made significant inroads into understanding sex-influenced immune responses. As physicians seek to provide more targeted patient care, it is critical to understand how sex-defining factors (e.g., chromosomes, gonadal hormones) alter immune responses in health and disease. In this review, we highlight recent insights into sex differences in autoimmunity; virus infection, specifically severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; and cancer immunotherapy. A deeper understanding of underlying mechanisms will allow the development of a sex-based approach to disease screening and treatment.

Keywords: autoimmunity; chromosomal complement; immune-related adverse events; immunity; sex differences; sex hormones.

Figure 1

Schematic of mechanisms underlying sex-related differences in immunity. Sex chromosome complement (e.g., 46XX or 46XY), gonads (ovaries or testes), and sex steroids (e.g., estrogens or androgens) contribute to sex differences in the immune response. The X and Y chromosomes differ in gene content, with many immune-related genes located on the X chromosome. Moreover, the degree to which a subset of X chromosome genes is expressed differs between cells, tissue types, and individuals, which adds complexity to chromosomal contributions to sex differences. Sex steroids influence lymphocyte development, proliferation, and activation. Collectively, these sex-specific factors modulate innate and adaptive immunity and subsequently alter outcomes of autoimmunity, viral infection, and cancer immunotherapy. Abbreviations: AIRE, autoimmune regulator; COVID-19, coronavirus disease 2019; ICI, immune checkpoint inhibitor; IFN, interferon; IrAE, immune-related adverse event; pDC, plasmacytoid dendritic cell; TCR, T cell receptor; TLR7, Toll-like receptor 7. Figure adapted from images created with BioRender.com.

Figure 2

Schematic of sex differences identified during COVID-19 infection. SARS-CoV-2 is internalized through interaction with ACE2. Following host cell entry, viral nucleic acids are detected by pattern recognition receptors, such as TLRs, and antiviral transcriptional programs are initiated. The innate and adaptive immune systems are successively activated to control viral infection. Sex differences have been identified at each stage of the immune response to SARS-CoV-2 infection. TLR7 escapes X inactivation and is more highly expressed in females. Type I interferon production by pDCs, T cell activation, and B cell class switching are also enhanced in females. TNF-α production, however, is enhanced in males. Abbreviations: ACE2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019; IFN, interferon; IRF, interferon regulatory factor; pDC, plasmacytoid dendritic cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Tfh, T follicular helper; TLR, Toll-like receptor. Figure adapted from images created with BioRender.com.