Inherent X-Linked Genetic Variability and Cellular Mosaicism Unique to Females Contribute to Sex-Related Differences in the Innate Immune Response

Abstract

Females have a longer lifespan and better general health than males. Considerable number of studies also demonstrated that, after trauma and sepsis, females present better outcomes as compared to males indicating sex-related differences in the innate immune response. The current notion is that differences in the immuno-modulatory effects of sex hormones are the underlying causative mechanism. However, the field remains controversial and the exclusive role of sex hormones has been challenged. Here, we propose that polymorphic X-linked immune competent genes, which are abundant in the population are important players in sex-based immuno-modulation and play a key role in causing sex-related outcome differences following trauma or sepsis. We describe the differences in X chromosome (ChrX) regulation between males and females and its consequences in the context of common X-linked polymorphisms at the individual as well as population level. We also discuss the potential pathophysiological and immune-modulatory aspects of ChrX cellular mosaicism, which is unique to females and how this may contribute to sex-biased immune-modulation. The potential confounding effects of ChrX skewing of cell progenitors at the bone marrow is also presented together with aspects of acute trauma-induced de novo ChrX skewing at the periphery. In support of the hypothesis, novel observations indicating ChrX skewing in a female trauma cohort as well as case studies depicting the temporal relationship between trauma-induced cellular skewing and the clinical course are also described. Finally, we list and discuss a selected set of polymorphic X-linked genes, which are frequent in the population and have key regulatory or metabolic functions in the innate immune response and, therefore, are primary candidates for mediating sex-biased immune responses. We conclude that sex-related differences in a variety of disease processes including the innate inflammatory response to injury and infection may be related to the abundance of X-linked polymorphic immune-competent genes, differences in ChrX regulation, and inheritance patterns between the sexes and the presence of X-linked cellular mosaicism, which is unique to females.

The role of gene expression on human sexual dimorphism: too early to call

“…Although no GO term showed significant enrichment after FDR correction, we found response to glucagon (GO:0033762, P=1.59x10 -03 ) and negative regulation of cytokine production (GO:1900016, P=2.43x10 -03 ) as the two most enriched (top 50 GO terms are reported in Supplementary Table 2). These pathways are involved in two sexually dimorphic processes: glucose metabolism and inflammatory response, respectively [21] [22].…”

Sex-bias in COVID-19: a meta-analysis and review of sex differences in disease and immunity

“…There is an over-expression of genes with an immune function on the X chromosome 64 , as evidenced by the existence of many X-linked immunodeficiency disorders 65 . There is emerging evidence that there may be variable inactivation and regulation of the inactive X chromosome in immune cells with subsequent bi-allelic expression of X-encoded immune genes in females 66,67 .…”

Risk-Adjustment for Swedish In-Hospital Trauma Mortality using International Classification of disease Injury Severity Score (ICISS) : issues with description and methods

“…[86][87][88][89] Two theories have been prevalent, the effect of the female sex hormone oestrogen, or the mosaic X chromosome theory. [59][60][61][62][63] However, clinically data have not been as convincing, as outcome advantages have been shown for both male and female trauma. For example, in burns both male and female survival advantages have been claimed based on registry studies.…”

“…However, the debate is ongoing about whether the protective model of female sex is the result of genetics or hormonal protection. [59][60][61][62][63] Paper IV evaluates the effect of sex on 30-day mortality.…”