Autoreactive murine Th1 and Th2 cells kill syngeneic macrophages and induce autoantibodies.
D10 cells, a cloned Th2 line, become autoreactive following treatment with DNA methylation inhibitors like 5-azacytidine (5-azaC), and induce anti-DNA antibodies if injected into unirradiated syngenic mice. The mechanism by which the autoreactive cells break tolerance is unknown. To further define effector functions required, we asked if 5-azaC-treated Th1 cells could also induce autoimmunity. AE7 cells, a cloned Th1 line, were treated with 5-azaC and shown to become autoreactive and induce anti-DNA antibodies in vivo. Comparison of effector mechanisms demonstrated that the two cell lines secreted a distinct repertoire of cytokines, and that only killing of syngeneic Mø was common to both AE7 and D10 cells. This suggests that Mø killing may be an early step in the induction of anti-DNA antibodies, providing antigenic nucleosomes and decreasing clearance of apoptotic material. Secretion of cytokines promoting B cell differentiation may play a role, but no one cytokine is required.
Yung
R
R
University of Michigan, Ann Arbor, USA.
Kaplan
M
M
Ray
D
D
Schneider
K
K
Mo
R R
RR
Johnson
K
K
Richardson
B
B
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D016923:Cell Death / Q000276:immunology; D002999:Clone Cells; D018920:Coculture Techniques; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000166:cytology*; D051379:Mice; D008815:Mice, Inbred Strains; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001323:Autoantibodies; D004791:Enzyme Inhibitors; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D000077209:Decitabine; D007371:Interferon-gamma; D001374:Azacitidine