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.
Richardson
Bruce
B
Department of Internal Medicine, University of Michigan and the Ann Arbor Veteran's Affairs Hospital, Ann Arbor, MI, USA.
Ray
Donna
D
Yung
Raymond
R
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