Brief Report: Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome

Sharma, Rohan; Harris, Valerie M.; Cavett, J. W.; Kurien, Biji T.; Liu, Ke; Koelsch, Kristi A.; Fayaaz, Anum; Chaudhari, Kaustubh S; Radfar, Lida; Lewis, David M.; Stone, Donald U.; Kaufman, C. Erick; Li, Shibo; Segal, Barbara; Wallace, Daniel J.; Weisman, Michael H.; Venuturupalli, Swamy; Kelly, Jennifer A.; Pons-Estel, Bernardo A.; Jönsson, Roland; Lu, Xin; Gottenberg, Jacques Éric; Anaya, Juan Manuel; Cunninghame-Graham, Deborah S.; Huang, Andrew J.W.; Brennan, Michael T.; Hughes, Pamela J.; Alevizos, Ilias; Miceli‐Richard, Corinne; Keystone, Edward; Bykerk, Vivian P.; Hirschfield, Gideon M.; Nordmark, Gunnel; Bucher, Sara Magnusson; Eriksson, Per; Omdal, Roald; Rhodus, Nelson L.; Rischmueller, Maureen; Rohrer, Michael D.; Wahren‐Herlenius, Marie; Witte, Torsten; Alarcón‐Riquelme, Marta E.; Mariette, Xavier; Lessard, Christopher J.; Harley, John B.; Ng, Wan Fai; Rasmussen, Astrid; Sivils, Kathy L.; Scofield, R. Hal

doi:10.1002/art.40207

Cited by 38 publications

(17 citation statements)

References 41 publications

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“… 5 , 53 Thus, several recent studies suggest that the female prevalence of Sjögren syndrome is due to an X-chromosome dose effect, and that individuals with X-chromosome abnormalities like triple X syndrome (47 XXX) and Klinefelter syndrome (47 XXY) have an increased risk for developing the disease. 61 – 63 In fact, attention has been drawn to X-chromosome vulnerability as a possible explanation for the high female prevalence of autoimmune diseases in general. 64 – 67 Therefore, the genes located on the X-chromosome are especially intriguing.…”

Section: Discussionmentioning

confidence: 99%

Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

Tellefsen

Morthen

Richards

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PurposeSjögren syndrome is an autoimmune disease that occurs primarily in women, and is associated with lacrimal gland inflammation and aqueous-deficient dry eye. We hypothesize that sex-associated differences in lacrimal gland gene expression are very important in promoting lymphocyte accumulation in this tissue and contribute to the onset, progression, and/or severity of the inflammatory disease process. To test our hypothesis, we explored the nature and extent of sex-related differences in gene expression in autoimmune lacrimal glands.MethodsLacrimal glands were collected from age-matched, adult, male and female MRL/MpJ-Tnfrsf6lpr (MRL/lpr) and nonobese diabetic/LtJ (NOD) mice. Glands were processed for the analysis of differentially expressed mRNAs by using CodeLink Bioarrays and Affymetrix GeneChips. Data were evaluated with bioinformatics and statistical software.ResultsOur results show that sex significantly influences the expression of thousands of genes in lacrimal glands of MRL/lpr and NOD mice. The immune nature of this glandular response is very dependent on the Sjögren syndrome model. Lacrimal glands of female, as compared with male, MRL/lpr mice contain a significant increase in the expression of genes related to inflammatory responses, antigen processing, and chemokine pathways. In contrast, it is the lacrimal tissue of NOD males, and not females, that presents with a significantly greater expression of immune-related genes.ConclusionsThese data support our hypothesis that sex-related differences in gene expression contribute to lacrimal gland disease in Sjögren syndrome. Our findings also suggest that factors in the lacrimal gland microenvironment are critically important in mediating these sex-associated immune effects.

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Section: Discussionmentioning

confidence: 99%

Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

Tellefsen

Morthen

Richards

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…Further, female trisomy (47,XXX) is also overrepresented in SLE as the prevalence in 47,XXX compared to karyotypically normal 46,XX women is 2.5:1. SS has a similar increased prevalence in trisomy females compared to normal females (2.9:1) . SLE has also been reported in polysomy‐X patients (48,XXXX) .…”

Section: The X Chromosome In Autoimmunitymentioning

confidence: 55%

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

Syrett

Anguera

2019

Journal of Leukocyte Biology

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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.

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“…On the other hand, an extra X chromosome can predispose to SLE even in the absence of abnormal sex hormones. Each additional X chromosome, which is normally inactivated by methylation, could exert an effect if methylation is reversed or if additional X chromosomes affect methylation-related regulation of autosomal genes [ 19 ]. In a study including 2500 patients, 3 of them had a triple mosaic consisting of 45, X/46, XX/47, XXX, suggesting more attention in genes within partial trisomy of the distal p arm of the X chromosome as the mediators of the X chromosome dose effect for sex bias in SLE [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Trisomy X in a patient with childhood-onset systemic lupus erythematosus

Barbosa

Sinicato

Julio

et al. 2020

Journal of Translational Autoimmunity

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Childhood-onset systemic lupus erythematosus (cSLE) is a rare, chronic and systemic autoimmune disease generally with a more severe clinical phenotype than the adult-onset SLE. In both conditions, it is known that females are predominantly affected; therefore, the possible overlap of SLE and sex chromosomal abnormalities has attracted attention. Our case report describe the clinical manifestations and immunological profile of a Brazilian female with cSLE and trisomy X. The 22 year-old patient, diagnosed with cSLE at age of 11, present some features related to 47, XXX, such as difficulties at school and communication, although this was not enough to investigate for chromosome abnormalities. Cytoscan HD array screening allowed the comprehensive diagnosis for this patient. We also characterized her ancestral composition, showing that she has 6.2% higher African component than the mean from health subjects from the same geographical area. This report reinforces the role of the X chromosome dose effect for sex bias in SLE, as well as the importance of African ancestry composition in cLES. It also throws lights upon the application of high-throughput molecular analysis in a large scale cohort can be useful to detect the impact of the genomic findings for more accurate epidemiological data.

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Brief Report: Rare X Chromosome Abnormalities in Systemic Lupus Erythematosus and Sjögren's Syndrome

Abstract: Very rare X chromosome abnormalities are present among patients with either SS or SLE and may inform the location of a gene(s) that mediates an X dose effect, as well as critical cell types in which such an effect is operative.

Cited by 38 publications

References 41 publications

Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

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

Trisomy X in a patient with childhood-onset systemic lupus erythematosus

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