Unlocking the mystery of systemic sclerosis

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Expression of genes related to X chromosome inactivation is linked to ISG scores in pDCs of women with SSc.

(A) The left panel shows where the XIST gene is active in single cells of pDCs using a UMAP plot. The right panel compares XIST expression levels between healthy individuals (HDs) and SSc patients.
(B and C) These panels compare the levels of SPEN, CBX4, and ING4 genes between healthy individuals and SSc patients.
(D) This panel compares XIST expression between groups of cells with low and high ISG scores.
(E) The left panel shows a comparison of SPEN expression between low and high ISG score groups. The right panel shows the relationship between SPEN levels and ISG scores.
(F) Similarly, the left panel compares CBX4 expression between low and high ISG score groups, and the right panel shows the relationship between CBX4 levels and ISG scores. Credit: J Exp Med (2025) 222 (3): e20231809. https://doi.org/10.1084/jem.20231809

Systemic sclerosis (SSc) is a complex autoimmune disease that primarily affects women. It is characterized by an overproduction of collagen, leading to the hardening and thickening of skin and other organs. Although the exact cause of SSc is unknown, researchers believe that a combination of genetic and environmental factors play a role.

One of the key factors contributing to the development of SSc is the chronic presence of type 1 interferons (IFN-I), a group of signaling proteins involved in immune responses. These proteins are produced by immune cells called plasmacytoid dendritic cells (pDCs). In individuals with SSc, pDCs are chronically activated and produce high levels of IFN-I, which can contribute to fibrosis and worsen the disease.

A recent study published in the Journal of Experimental Medicine investigated the role of pDCs and a process called X-chromosome inactivation (XCI) in SSc. XCI is a process that occurs in females where one of the two X chromosomes in each cell is randomly inactivated to ensure that females, like males, only have one active copy of most X-linked genes. This process is important for maintaining normal cellular function. However, some genes on the inactive X chromosome can escape inactivation, leading to higher expression levels of these genes in females.

The study found that in pDCs of women with SSc, there is an increased frequency of escape from XCI at the TLR7/8 locus, a region on the X chromosome that contains genes for proteins involved in immune responses. TLR7 and TLR8 are proteins that can detect viral and bacterial components and trigger the production of IFN-I. The study showed that the escape from XCI at the TLR7/8 locus resulted in higher expression levels of TLR7 and TLR8 in pDCs of women with SSc. This increased expression of TLR7 and TLR8 was associated with changes in the 3D organisation of the inactive X chromosome, suggesting that higher-order loop formation is linked to gene expression from the inactive X chromosome.

Furthermore, the researchers found that the expression levels of XIST and SPEN, key regulators of XCI, were reduced in pDCs of women with SSc. XIST is a long non-coding RNA that coats the inactive X chromosome and initiates the silencing of genes on this chromosome. SPEN is a protein that binds to XIST and recruits other proteins involved in gene silencing. The reduced expression levels of XIST and SPEN in pDCs of women with SSc suggest that the XCI process is dysregulated in these cells, potentially contributing to the increased expression of TLR7 and TLR8.

The findings of this study suggest that altered XCI at the TLR7/8 locus may contribute to the chronic IFN-I activity of pDCs in women with SSc. This dysregulation of XCI could explain, at least in part, the higher prevalence of SSc in women. The study also highlights the importance of understanding the role of XCI in autoimmune diseases and suggests that targeting TLR7 and TLR8 could be a potential therapeutic strategy for SSc.

More research is needed to fully understand the complex interplay between XCI, pDCs, and IFN-I in the development of SSc. However, this study provides valuable insights into the underlying mechanisms of this disease and paves the way for the development of new and more effective treatments.

More information: Altered X-chromosome inactivation of the TLR7/8 locus and heterogeneity of pDCs in systemic sclerosis. J Exp Med (2025) 222 (3): e20231809. https://doi.org/10.1084/jem.20231809

Journal information: https://rupress.org/jem
Location: Oxford, UK

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