| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
* Department of Dermatology, Second Xiangya Hospital, Central South University, Changsha, 41011 Hunan, China;
Department of Medicine, University of Michigan, Ann Arbor, MI;
Departments of Medicine and Pediatrics, Massachusetts General Hospital, Boston, MA 02114; and
Department of Medicine, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, MI 48109
Why systemic lupus erythematosus primarily affects women is unknown. Recent evidence indicates that human lupus is an epigenetic disease characterized by impaired T cell DNA methylation. Women have two X chromosomes; one is inactivated by mechanisms including DNA methylation. We hypothesized that demethylation of sequences on the inactive X may cause gene overexpression uniquely in women, predisposing them to lupus. We therefore compared expression and methylation of CD40LG, a B cell costimulatory molecule encoded on the X chromosome, in experimentally demethylated T cells from men and women and in men and women with lupus. Controls included TNFSF7, a methylation-sensitive autosomal B cell costimulatory molecule known to be demethylated and overexpressed in lupus. Bisulfite sequencing revealed that CD40LG is unmethylated in men, while women have one methylated and one unmethylated gene. 5-Azacytidine, a DNA methyltransferase inhibitor, demethylated CD40LG and doubled its expression on CD4+ T cells from women but not men, while increasing TNFSF7 expression equally between sexes. Similar studies demonstrated that CD40LG demethylates in CD4+ T cells from women with lupus, and that women but not men with lupus overexpress CD40LG on CD4+ T cells, while both overexpress TNFSF7. These studies demonstrate that regulatory sequences on the inactive X chromosome demethylate in T cells from women with lupus, contributing to CD40LG overexpression uniquely in women. Demethylation of CD40LG and perhaps other genes on the inactive X may contribute to the striking female predilection of this disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Public Health Service Grants AR42525, ES015214, AG25877, and P30AR048310, a grant from the Veterans Administration (to B.R.), and Grant 30671883 from the National Natural Science Foundation of China (to Q.L.).
2 Address correspondence and reprint requests to Dr. Bruce Richardson, Department of Medicine, University of Michigan, 3007 Biomedical Science Research Building, Ann Arbor, MI 48109-2200. E-mail address: Brichard{at}umich.edu
3 Abbreviations used in this paper: SLEDAI, Systemic Lupus Erythematosus Disease Activity Index; 5-azaC, 5-azacytidine; MFI, mean fluorescence intensity; MS-PCR, methylation-sensitive PCR.
This article has been cited by other articles:
|
|
 |
|
  S. Garaud, C. Le Dantec, S. Jousse-Joulin, C. Hanrotel-Saliou, A. Saraux, R. A. Mageed, P. Youinou, and Y. Renaudineau IL-6 Modulates CD5 Expression in B Cells from Patients with Lupus by Regulating DNA Methylation J. Immunol., May 1, 2009; 182(9): 5623 - 5632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Migeon X Inactivation, Female Mosaicism, and Sex Differences in Renal Diseases J. Am. Soc. Nephrol., November 1, 2008; 19(11): 2052 - 2059. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
