title: Murine models of lupus induced by hypomethylated T cells (DNA hypomethylation and lupus…).
abstract: CD4+ T cell DNA hypomethylation may contribute to the development of drug induced and idiopathic human lupus. Inhibiting DNA methylation in mature CD4+ T cells causes MHC-specific autoreactivity in vitro. The lupus-inducing drugs hydralazine and procainamide also inhibit T cell DNA methylation and induce autoreactivity, and T cells from patients with active lupus have hypomethylated DNA and a similarly autoreactive T cell subset. Further, T cells treated with DNA methylation inhibitors demethylate the same sequences that demethylate in T cells from patients with active lupus. The pathologic significance of the autoreactivity induced by inhibiting T cell DNA methylation has been tested by treating murine T cells in vitro with drugs which modify DNA methylation, then injecting the cells into syngeneic female mice. Mice receiving CD4+ T cells demethylated by a variety of agents including procainamide and hydralazine develop a lupus-like disease. Further, transgenic mice with an inducible T cell DNA methylation defect also develop lupus-like autoimmunity. This chapter describes the protocols for inducing autoreactivity in murine T cells in vitro and for inducing autoimmunity in vivo using an adoptive transfer approach or transgenic animal models.
authors.affiliation: University of Michigan and the Ann Arbor Veteran's Affairs Hospital, Ann Arbor, MI, USA. brichard@umich.edu
authors.forename: Bruce
authors.initials: B
authors.lastname: Richardson
authors.forename: Amr H
authors.initials: AH
authors.lastname: Sawalha
authors.forename: Donna
authors.initials: D
authors.lastname: Ray
authors.forename: Raymond
authors.initials: R
authors.lastname: Yung
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D001374:Azacitidine / Q000494:pharmacology; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D001374:Azacitidine