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. 2024 Sep 30;83(10):1315-1321.
doi: 10.1136/ard-2024-225585.

Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus

Amy L Roberts  1 , Alessandro Morea  2   3 , Ariella Amar  4 , Magdalena West  4 , Sarah Karrar  4 , Rhiannon Lehane  4 , Philip Tombleson  4 , Deborah Cunningham Grahman  4 , John A Reynolds  5 , Chloe C Y Wong  6 , David L Morris  7 , Kerrin S Small #  1 , Timothy J Vyse #  8
Affiliations

Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus

Amy L Roberts et al. Ann Rheum Dis. .

Abstract

Objectives: Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism.

Methods: We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms.

Results: Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10-5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression.

Conclusions: These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.

Keywords: Autoimmune Diseases; Lupus Erythematosus, Systemic; Polymorphism, Genetic.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1. XCI-skewing in SLE and controls The correlation between XCI (y-axis) and age (x-axis) is shown in panels on the left and the proportions of individuals (y-axis) with random (50%–79%), skewed (80%–89%) and extremely skewed (>90%) XCI across increasing age groups (x-axis) are shown in panels on the right. Controls (n=796) are in the upper panels and SLE cases (n=181) are in the lower panels. SLE, systemic lupus erythematosus; XCI, X chromosome inactivation.
Figure 2
Figure 2. XCI-skewing in a discordant twin study using age-matched twin pairs discordant for SLE (Npairs =10), disease status is associated with decreased XCI skewing in the intratwin analysis of DZ twins (one-sided paired samples Wilcoxon test; p=0.016) but not MZ twins (one-sided paired samples Wilcoxon test; p=0.94). DZ, dizygotic; MZ, monozygotic; SLE, systemic lupus erythematosus; XCI, X chromosome inactivation.
Figure 3
Figure 3. The effect of disease severity on XCI-skewing boxplots representing the association of renal disease as a marker of SLE severity on XCI skewing. All boxplots display the median and IQR, with XCI-skewing on the y-axis and age category on the x axis. SLE, systemic lupus erythematosus; XCI, X chromosome inactivation.
Figure 4
Figure 4. The age-dependent effects of IFN-signalling on XCI-skewing boxplots representing the association of non-linear sSIGLEC-1 percentile groups on XCI-skewing. All boxplots display the median and IQR, with XCI-skewing on the y-axis, and percentile groups on the x-axis. XCI, X chromosome inactivation.
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