When the balance is broken: X-linked gene dosage from two X chromosomes and female-biased autoimmunity

Abstract

Women and men exhibit differences in innate and adaptive immunity, and women are more susceptible to numerous autoimmune disorders. Two or more X chromosomes increases the risk for some autoimmune diseases, and increased expression of some X-linked immune genes is frequently observed in female lymphocytes from autoimmune patients. Evidence from mouse models of autoimmunity also supports the idea that increased expression of X-linked genes is a feature of female-biased autoimmunity. Recent studies have begun to elucidate the correlation between abnormal X-chromosome inactivation (XCI), an essential mechanism female somatic cells use to equalize X-linked gene dosage between the sexes, and autoimmunity in lymphocytes. In this review, we highlight research describing overexpression of X-linked immunity-related genes and female-biased autoimmunity in both humans and mouse models, and make connections with our recent work elucidating lymphocyte-specific mechanisms of XCI maintenance that become altered in lupus patients. K E Y W O R D Slupus, mouse models of lupus disease, sexual dimorphism with immune disease, X-chromosome inactivation, XCI gene escape, Xist RNA important for the development of autoimmunity, and disease results from additive effects of several risk variants, which alone would be insufficient to cause disease. Yet, hundreds of loci have been associated with autoimmune diseases, and some of these immune gene variants are present in different diseases, suggesting that common J Leukoc Biol. 2019;106:919-932.

X-linked diseases: susceptible females

“…It seems that expression of the Toll-like receptors on the inactive X is partly responsible for the impressive sex differences in some cases of autoimmune diseases like Lupus and Sjogren disease. 36 Toll-like receptors, encoded by the X chromosome, are signaling pattern recognition receptors that are an integral part of innate immunity. The little extra activity may provide females with better protection against infectious agents, but it may make them more susceptible to autoimmunity.…”

“…Studies in mice show that increasing the expression of the X-linked Toll-like receptors in susceptible mice increases the expression of the autoimmune disorder. 36 It has not yet been shown that affected females and Klinefelter males have greater expression of their Toll-like receptors than those women and XXY males who do not have the disorder.…”

Forged by DXZ4, FIRRE, and ICCE: How Tandem Repeats Shape the Active and Inactive X Chromosome

“…Firre RNA primarily regulates autosomal genes in the hematopoietic system, including in common lymphoid progenitors (Andergassen et al, 2019;Lewandowski et al, 2019). This observation may prove relevant to sex differences in autoimmune disorders (Syrett and Anguera, 2019), as the FIRRE locus was also recently identified as differentially methylated in CD4 + memory T cells of twins discordant for multiple sclerosis (Souren et al, 2019). While global trans-acting FIRRE/Firre RNA functions are well beyond the scope of this perspective, it appears that many autosomal targets function in RNA splicing, processing and transport, likely due to FIRRE/Firre RNAs physical association with HNRNPU (Hacisuleyman et al, 2014;Bergmann et al, 2015).…”

X Inactivation and Escape: Epigenetic and Structural Features

“…In terms of disease susceptibility there is ample evidence suggesting that sex bias in X-linked gene expression play a role. For example, having two X chromosomes increases the risk of developing autoimmunity [reviewed in Syrett and Anguera (2019)]. This phenomenon may be a result of unusual XCI patterns in immune cells, which could leave certain X-linked genes involved in immune response susceptible to reactivation (Wang et al, 2016; Syrett et al, 2019).…”