title: Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus.
abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease primarily afflicting women. The reason for the gender bias is unclear, but genetic susceptibility, estrogen and environmental agents appear to play significant roles in SLE pathogenesis. Environmental agents can contribute to lupus susceptibility through epigenetic mechanisms. We used (C57BL/6xSJL)F1 mice transgenic for a dominant-negative MEK (dnMEK) that was previously shown to be inducibly and selectively expressed in T cells. In this model, induction of the dnMEK by doxycycline treatment suppresses T cell ERK signaling, decreasing DNA-methyltransferase expression and resulting in DNA demethylation, overexpression of immune genes Itgal (CD11a) and Tnfsf7 (CD70), and anti-dsDNA antibody. To examine the role of gender and estrogen in this model, male and female transgenic mice were neutered and implanted with time-release pellets delivering placebo or estrogen. Doxycycline induced IgG anti-dsDNA antibodies in intact and neutered, placebo-treated control female but not male transgenic mice. Glomerular IgG deposits were also found in the kidneys of female but not male transgenic mice, and not in the absence of doxycycline. Estrogen enhanced anti-dsDNA IgG antibodies only in transgenic, ERK-impaired female mice. Decreased ERK activation also resulted in overexpression and demethylation of the X-linked methylation-sensitive gene CD40lg in female but not male mice, consistent with demethylation of the second X chromosome in the females. The results show that both estrogen and female gender contribute to the female predisposition in lupus susceptibility through hormonal and epigenetic X-chromosome effects and through suppression of ERK signaling by environmental agents.
authors.affiliation: Department of Internal Medicine, Rheumatology Division, The University of Michigan, Ann Arbor, MI 48109-2200, USA. fmstrick@umich.edu
authors.forename: Faith M
authors.initials: FM
authors.lastname: Strickland
authors.forename: Anura
authors.initials: A
authors.lastname: Hewagama
authors.forename: Qianjian
authors.initials: Q
authors.lastname: Lu
authors.forename: Ailing
authors.initials: A
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Hinderer
authors.forename: Ryan
authors.initials: R
authors.lastname: Webb
authors.forename: Kent
authors.initials: K
authors.lastname: Johnson
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.forename: Colin
authors.initials: C
authors.lastname: Delaney
authors.forename: Raymond
authors.initials: R
authors.lastname: Yung
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Richardson
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D004195:Disease Models, Animal; D004781:Environmental Exposure; D044127:Epigenesis, Genetic; D004967:Estrogens / Q000633:toxicity*; D005260:Female; D015870:Gene Expression; D059647:Gene-Environment Interaction; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012737:Sex Factors; D014960:X Chromosome
chemical_list: D000974:Antibodies, Antinuclear; D004967:Estrogens