SeXY chromosomes and the immune system: reflections after a comparative study

Abstract

Background: Sex bias in immune function has been contributed in part to a preponderance of immune systemrelated genes (ISRG) on the X-chromosome. We verified whether ISRG are more abundant on the X chromosome as compared to autosomal chromosomes and reflected on the impact of our findings. Methods: Consulting freely accessible databases, we performed a comparative study consisting of three complementary strategies. First, among coding X/Y-linked genes, the abundance of ISRG was compared to the abundance of genes dedicated to other systems. Genes were assigned considering three criteria: disease, tissue expression, and function (DEF approach). In addition, we carried out two genome-wide approaches to compare the contribution of sex and autosomal chromosomes to immune genes defined by an elevated expression in lymphatic tissues (LTEEG approach) or annotation to an immune system process, GO:0002376 (GO approach).Results: The X chromosome had less immune genes than the median of the autosomal chromosomes. Among Xlinked genes, ISRG ranked fourth after the reproductive and nervous systems and genes dedicated to development, proliferation and apoptosis. On the Y chromosome, ISRG ranked second, and at the pseudoautosomal region (PAR) first. According to studies on the expression of X-linked genes in a variety of (mostly non-lymphatic) tissues, almost two-thirds of ISRG are expressed without sex bias, and the remaining ISRG presented female and male bias with similar frequency. Various epigenetic controllers, X-linked MSL3 and Y-linked KDM5D and UTY, were preferentially expressed in leukocytes and deserve further attention for a possible role in sex biased expression or its neutralisation. Conclusions: The X chromosome is not enriched for ISRG, though particular X-linked genes may be responsible for sex differences in certain immune responses. So far, there is insufficient information on sex-biased expression of X/ Y-linked ISRG in leukocytes to draw general conclusions on the impact of X/Y-linked ISRG in immune function. More research on the regulation of the expression X-linked genes is required with attention to 1) female and male mechanisms that may either augment or diminish sex biased expression and 2) tissue-specific expression studies.

COVID-19 and Individual Genetic Susceptibility/Receptivity: Role of ACE1/ACE2 Genes, Immunity, Inflammation and Coagulation. Might the Double X-Chromosome in Females Be Protective against SARS-CoV-2 Compared to the Single X-Chromosome in Males?

“…However, since sex dimorphism observed in several inflammatory diseases, including respiratory pathologies, has also been confirmed in studies dealing with pre-pubertal cohorts [145][146][147], there is growing consensus on the need to consider additional factors/variables that may occur. Similarly, there is growing evidence suggesting that the X-chromosome and X-linked genes are the main determinants of the reported sex dimorphism in disease susceptibility and prognosis [8,148]. The X-chromosome carries about 1,200 genes [149] including cytokines/cytokines receptors, toll-like receptor (TLR)-mediated signaling pathway genes, NF-kB and MAPK signaling genes, genes involved in apoptosis, genes involved in redox balance, and other immune-modulators such as CD40 ligand and FOXP3, as recently reviewed [150].…”

Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19

“…Additionally, the X chromosome encodes a high density of immune-related genes and microRNAs which, despite inactivation of the second X chromosome in females, remain overly expressed in females compared to males, contributing to the heightened immune response in females [ [136] , [137] , [138] ]. The male-specific Y chromosome, which encodes substantially less genes than its X chromosome counterpart, has also been found to influence immune function as Y chromosome genes are expressed in various immune cell types and have been shown to alter immune function [ 139 , 140 ].…”

Sex differences in SARS-CoV-2 infection rates and the potential link to prostate cancer

“…In summary, females exhibit robust innate and adaptive immune responses to viral infections. Elevated transcriptional activation of immune response genes on the X-chromosome and sex-specific steroids like estrogens, help to facilitate faster clearance of viral loads in females 70 .…”