Murine models of lupus induced by hypomethylated T cells.
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 autoreactivity specific to the major histocompatibility complex 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 pathological significance of the autoreactivity induced by inhibiting T-cell DNA methylation has been tested by treating murine T cells in vitro with drugs that 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 lupuslike disease. This chapter describes the protocols for inducing autoreactivity in murine T cells in vitro and using the cells to induce autoimmunity in vivo.
Department of Internal Medicine, University of Michigan and the Ann Arbor Veteran's Affairs Hospital, Ann Arbor, MI, USA.
Bruce
B
Richardson
Donna
D
Ray
Raymond
R
Yung
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015551:Autoimmunity; D001374:Azacitidine / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D002460:Cell Line; D019175:DNA Methylation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008806:Mice, Inbred AKR; D008811:Mice, Inbred DBA
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D001374:Azacitidine