Treating activated CD4+ T cells with either of two distinct DNA methyltransferase inhibitors, 5-azacytidine or procainamide, is sufficient to cause a lupus-like disease in syngeneic mice.
Human antigen-specific CD4+ T cells become autoreactive after treatment with various DNA methylation inhibitors, including 5-azacytidine, procainamide, and hydralazine. This suggests a mechanism that could contribute to the development of some forms of autoimmunity. In this report we have asked whether T cells treated with DNA methylation inhibitors can induce autoimmunity. Murine CD4+ T cells were treated with 5-azacytidine or procainamide and were shown to respond to syngeneic antigen-presenting cells, similar to CD4+ human T cell clones treated with these drugs. Functional characterization demonstrated that cells treated with either drug spontaneously lysed syngeneic macrophages and secreted IL-4, IL-6, and IFN-gamma. Adoptive transfer of 5-azacytidine- or procainamide-treated cells into unirradiated syngeneic recipients induced an immune complex glomerulonephritis and IgG anti-DNA and antihistone antibodies. These experiments demonstrate that T cells treated with either of two distinct DNA methyltransferase inhibitors are sufficient to induce a lupus-like disease. It is possible that the lysis of macrophages, together with the release of cytokines promoting B cell differentiation, contributes to the autoantibody production and immune complex deposition. These results suggest that environmental agents that inhibit DNA methylation could interact with T cells in vivo to produce a lupus-like illness, a mechanism that could have relevance to drug-induced and idiopathic lupus.
Quddus
J
J
Department of Internal Medicine, University of Michigan, Ann Arbor 48109.
Johnson
K J
KJ
Gavalchin
J
J
Amento
E P
EP
Chrisp
C E
CE
Yung
R L
RL
Richardson
B C
BC
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001374:Azacitidine / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D005260:Female; D007116:Immunization, Passive; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D011342:Procainamide / Q000494:pharmacology*
D004248:DNA (Cytosine-5-)-Methyltransferases; D011342:Procainamide; D001374:Azacitidine