Mature dendritic cells readily break tolerance in normal mice but do not lead to disease expression.
OBJECTIVE
To examine the ability of mature dendritic cells (DCs) or macrophages intentionally exposed to lipopolysaccharide or apoptotic or necrotic cells to break tolerance in normal mice.


METHODS
We adoptively transferred into C57BL/6 mice a variety of syngeneic myeloid antigen-presenting cell populations exposed to different activation stimuli as well as to meals of necrotic and apoptotic cells. We studied expression of autoimmunity in the immunized mice by serologic evaluation of autoantibody production, subclass analysis of Ig production, clinical evidence of kidney disease, glomerular immune complex deposition, and renal pathology.


RESULTS
Injection of mice with DCs incubated with apoptotic or necrotic cells, as well as, surprisingly, with DCs cultured in media alone, induced high levels of IgG autoantibodies, including anti-double-stranded DNA (anti-dsDNA) antibodies. In striking contrast, transfer of equivalent-treated macrophages failed to generate IgG autoantibodies. IgG was deposited in the kidneys of mice vaccinated with DCs, but despite high levels of anti-dsDNA antibodies, these mice did not develop overt nephritis. Serologic evaluation of the antibody response revealed that the mice primarily developed elevated levels of IgG1 antibodies, including high levels of IgG1 anti-dsDNA.


CONCLUSIONS
The data suggest that mature myeloid DCs are able to break tolerance and induce lupus autoantibodies in normal hosts, but that other susceptibility factors must be in place to induce long-lasting autoimmunity and clinical expression of disease.
Georgiev
Maria
M
Hospital for Special Surgery, Weill Medical College of Cornell University, 535 East 70th Street, New York, NY 10021, USA.
Agle
Lucila M A
LM
Chu
Jia Li
JL
Elkon
Keith B
KB
Ashany
Dalit
D
D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000096:biosynthesis*; D001854:Bone Marrow Cells / Q000276:immunology; D002477:Cells / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000378:metabolism; D007267:Injections; D007678:Kidney Glomerulus / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010587:Phagocytosis
D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D008070:Lipopolysaccharides