Sexual Dimorphism in Innate Immunity: The Role of Sex Hormones and Epigenetics

Abstract

Sexual dimorphism refers to differences between biological sexes that extend beyond sexual characteristics. In humans, sexual dimorphism in the immune response has been well demonstrated, with females exhibiting lower infection rates than males for a variety of bacterial, viral, and parasitic pathogens. There is also a substantially increased incidence of autoimmune disease in females compared to males. Together, these trends indicate that females have a heightened immune reactogenicity to both self and non-self-molecular patterns. However, the molecular mechanisms driving the sexually dimorphic immune response are not fully understood. The female sex hormones estrogen and progesterone, as well as the male androgens, such as testosterone, elicit direct effects on the function and inflammatory capacity of immune cells. Several studies have identified a sex-specific transcriptome and methylome, independent of the well-described phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism also occurs at the epigenetic level. Moreover, distinct alterations to the transcriptome and epigenetic landscape occur in synchrony with periods of hormonal change, such as puberty, pregnancy, menopause, and exogenous hormone therapy. These changes are also mirrored by changes in immune cell function. This review will outline the evidence for sex hormones and pregnancy-associated hormones as drivers of epigenetic change, and how this may contribute to the sexual dimorphism. Determining the effects of sex hormones on innate immune function is important for understanding sexually dimorphic autoimmune diseases, sex-specific responses to pathogens and vaccines, and how innate immunity is altered during periods of hormonal change (endogenous or exogenous).

MYD88, NFKB1, and IL6 transcripts overexpression are associated with poor outcomes and short survival in neonatal sepsis

“…The present finding of MYD88 upregulation showed sex disparity with significantly higher levels in male neonates than females, contributing to the previous observations in which females exhibited a less exaggerated immune response than males 17 , 18 . While the exact mechanism underlying this observation is not conclusive, hormonal and epigenetic factors were proposed to contribute to this phenomenon by impacting the pathogen-specific inflammatory responses (particularly lipopolysaccharides) and the immunological differences 18 – 20 . Naugler et al have found that "MYD88-dependent activation of IL6 production" could be negatively regulated by estrogen in their model of hepatocellular carcinoma induced by liver inflammation 21 .…”

Neurologic adverse events among 704,003 first-dose recipients of the BNT162b2 mRNA COVID-19 vaccine in Mexico: A nationwide descriptive study

“…Genetic and hormonal differences influence response to self and exogenous antigens. Women are more susceptible to autoimmune disease but have lower infection rates and better antibody response to vaccines than men [ 33 , 34 ]. Alas, women consistently report more vaccine-related adverse events [ 35 ].…”

Impact of the rs1024611 Polymorphism of CCL2 on the Pathophysiology and Outcome of Primary Myelofibrosis

“…Indeed, the fact that the homozygosity for the SNP qualifies as a host predisposition factor for the disease only in the male cohort may hint at the presence of a sex-related background that elicits (males) or mitigates (females) the effect of the SNP. In this context, several studies have identified a sex-specific transcriptome and methylome, which acts independently from the well-characterized phenomenon of X-chromosome inactivation, suggesting that sexual dimorphism also occurs at the epigenetic level [ 37 ].…”