DNA demethylation of CD40L in CD4+ T cells from women with systemic sclerosis: A possible explanation for female susceptibility

Objective Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not wel...

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Published inArthritis & rheumatology (Hoboken, N.J.) Vol. 64; no. 7; pp. 2338 - 2345
Main Authors Lian, XiaoRi, Xiao, Rong, Hu, Xinhong, Kanekura, Takuro, Jiang, HongYan, Li, YaPing, Wang, YaoYao, Yang, Yan, Zhao, Ming, Lu, QianJin
Format Journal Article
LanguageEnglish
Published Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2012
Wiley
Wiley Subscription Services, Inc
Subjects
Adult
Biological and medical sciences
CD4-Positive T-Lymphocytes - immunology
CD40 Ligand - genetics
Chromosomes
Deoxyribonucleic acid
Disease Susceptibility
Diseases of the osteoarticular system
DNA
DNA methylation
DNA Methylation - genetics
DNA Methylation - immunology
Female
Gene Expression Regulation
Humans
Lymphocytes
Male
Medical research
Medical sciences
Middle Aged
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Scleroderma, Systemic - genetics
Scleroderma, Systemic - immunology
Sex Factors
Human
Immunopathology
Connective tissue disease
Skin disease
Rheumatology
Autoimmune disease
Immunological investigation
DNA
Systemic disease
T-Lymphocyte
Female
Woman
Scleroderma
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Abstract Objective Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up‐regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc. Methods CD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real‐time reverse transcription–polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region. Results CD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated. Conclusion Demethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc.
AbstractList Objective Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up-regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc. Methods CD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real-time reverse transcription-polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region. Results CD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated. Conclusion Demethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc. [PUBLICATION ABSTRACT]
Objective Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up-regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc. Methods CD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real-time reverse transcription-polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region. Results CD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated. Conclusion Demethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc.
Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up-regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc. CD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real-time reverse transcription-polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region. CD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated. Demethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc.
Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up-regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc.OBJECTIVESystemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up-regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc.CD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real-time reverse transcription-polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region.METHODSCD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real-time reverse transcription-polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region.CD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated.RESULTSCD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated.Demethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc.CONCLUSIONDemethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc.
Objective Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the development of SSc. Although CD40L is overexpressed in patients with SSc, the mechanisms leading to this overexpression are not well understood. We previously demonstrated that DNA demethylation reactivates the silent X chromosome, resulting in CD40L overexpression in healthy women. We hypothesized that CD40L up‐regulation by DNA demethylation and subsequent reactivation of the silent X chromosome in female patients with SSc explain the susceptibility of women to SSc. The aim of this study was to investigate the effect of DNA demethylation on CD40L expression in CD4+ T cells from female patients with SSc. Methods CD40L expression in CD4+ T cells from patients with SSc and healthy control subjects was measured by flow cytometry and real‐time reverse transcription–polymerase chain reaction. Bisulfite sequencing was performed to determine the methylation status of the CD40L regulatory region. Results CD40L expression was significantly elevated in female patients with SSc. The methylation levels of the DNA regulatory sequences were reduced in female patients with SSc compared with healthy women, and there was a significant inverse correlation between the average methylation level and CD40L mRNA expression in female patients with SSc. In contrast, no significant difference was observed in the expression of CD40L between male patients with SSc and male control subjects. The DNA regulatory regions in both male patients and male control subjects were largely unmethylated. Conclusion Demethylation of CD40L regulatory elements on the inactive X chromosome contributes to CD40L overexpression in CD4+ T cells from female patients with SSc.
Author Lu, QianJin
Lian, XiaoRi
Wang, YaoYao
Zhao, Ming
Hu, Xinhong
Yang, Yan
Jiang, HongYan
Xiao, Rong
Li, YaPing
Kanekura, Takuro
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1529-0131
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IsPeerReviewed true
IsScholarly true
Issue 7
Keywords Human
Immunopathology
Connective tissue disease
Skin disease
Rheumatology
Autoimmune disease
Immunological investigation
DNA
Systemic disease
T-Lymphocyte
Female
Woman
Scleroderma
Language English
License http://onlinelibrary.wiley.com/termsAndConditions#vor
CC BY 4.0
Copyright © 2012 by the American College of Rheumatology.
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Sakkas LI, Xu B, Arlett CM, Lu S, Jimenez SA, Platsoucas CD. Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol 2002; 168: 3649-59.
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Valentini G, Romano MF, Naclerio C, Bisogni R, Lamberti A, Turco MC, et al. Increased expression of CD40 ligand in activated CD4+ T lymphocytes of systemic sclerosis patients. J Autoimmun 2000; 15: 61-6.
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Toubi E, Shoenfeld Y. The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 2004; 37: 457-67.
Lei W, Luo Y, Lei W, Luo Y, Yan K, Zhao S, et al. Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Scand J Rheumatol 2009; 38: 369-74.
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References_xml – reference: Lu Q, Kaplan M, Ray D, Ray D, Zacharek S, Gutsch D, et al. Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum 2002; 46: 1282-91.
– reference: Cipriani P, Marrelli A, Liakouli V, Di Benedetto P, Giacomelli R. Cellular players in angiogenesis during the course of systemic sclerosis. Autoimmun Rev 2011; 10: 641-6.
– reference: Cerutti A, Puga I, Cols M. Innate control of B cell responses. Trends Immunol 2011; 32: 202-11.
– reference: Hellman A, Chess A. Gene body-specific methylation on the active X chromosome. Science 2007; 315: 1141-3.
– reference: Bosello S, De Luca G, Tolusso B, Lama G, Angelucci C, Sica G, et al. B cells in systemic sclerosis: a possible target for therapy. Autoimmun Rev 2011; 10: 624-30.
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– reference: Robertson KD. DNA methylation and chromatin: unraveling the tangled web. Oncogene 2002; 21: 5361-79.
– reference: Chang SC, Tucker T, Thorogood NP, Brown CJ. Mechanisms of X-chromosome inactivation. Front Biosci 2006; 11: 852-66.
– reference: Toubi E, Shoenfeld Y. The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 2004; 37: 457-67.
– reference: Lei W, Luo Y, Lei W, Luo Y, Yan K, Zhao S, et al. Abnormal DNA methylation in CD4+ T cells from patients with systemic lupus erythematosus, systemic sclerosis, and dermatomyositis. Scand J Rheumatol 2009; 38: 369-74.
– reference: Miga A, Masters S, Gonzalez M, Noelle RJ. The role of CD40-CD154 interactions in the regulation of cell mediated immunity. Immunol Invest 2000; 29: 111-4.
– reference: Brooks WH, Le Dantec C, Pers JO, Youinou P, Renaudineau Y. Epigenetics and autoimmunity. J Autoimmun 2010; 34: J207-19.
– reference: Valentini G, Romano MF, Naclerio C, Bisogni R, Lamberti A, Turco MC, et al. Increased expression of CD40 ligand in activated CD4+ T lymphocytes of systemic sclerosis patients. J Autoimmun 2000; 15: 61-6.
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– reference: Komura K, Sato S, Hasegawa M, Fujimoto M, Takehara K. Elevated circulating CD40L concentrations in patients with systemic sclerosis. J Rheumatol 2004; 31: 514-9.
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Snippet Objective Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be...
Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be involved in the...
Objective Systemic sclerosis (SSc) is an autoimmune disease with a predilection for women. The interaction between CD40 and CD154 (CD40L) is known to be...
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SubjectTerms Adult
Biological and medical sciences
CD4-Positive T-Lymphocytes - immunology
CD40 Ligand - genetics
Chromosomes
Deoxyribonucleic acid
Disease Susceptibility
Diseases of the osteoarticular system
DNA
DNA methylation
DNA Methylation - genetics
DNA Methylation - immunology
Female
Gene Expression Regulation
Humans
Lymphocytes
Male
Medical research
Medical sciences
Middle Aged
Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis
Scleroderma, Systemic - genetics
Scleroderma, Systemic - immunology
Sex Factors
Title DNA demethylation of CD40L in CD4+ T cells from women with systemic sclerosis: A possible explanation for female susceptibility
URI https://api.istex.fr/ark:/67375/WNG-VW2ZXKC4-C/fulltext.pdf
https://onlinelibrary.wiley.com/doi/abs/10.1002%2Fart.34376
https://www.ncbi.nlm.nih.gov/pubmed/22231486
https://www.proquest.com/docview/1517117747
https://www.proquest.com/docview/1022839890
https://www.proquest.com/docview/1534837304
Volume 64
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