Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus.
Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA and the RNA-containing Smith antigen (Sm), may be selectively targeted in systemic lupus erythematosus because of their ability to activate a putative common receptor. Toll-like receptor 9 (TLR9), a receptor for CpG DNA, has been implicated in the activation of autoreactive B cells in vitro, but its role in promoting autoantibody production and disease in vivo has not been determined. We show that in TLR9-deficient lupus-prone mice, the generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited. Other autoantibodies, such as anti-Sm, are maintained and even increased in TLR9-deficient mice. In contrast, ablation of TLR3, a receptor for dsRNA, did not inhibit the formation of autoantibodies to either RNA- or DNA-containing antigens. Surprisingly, we found that despite the lack of anti-dsDNA autoantibodies in TLR9-deficient mice, there was no effect on the development of clinical autoimmune disease or nephritis. These results demonstrate a specific requirement for TLR9 in autoantibody formation in vivo and indicate a critical role for innate immune activation in autoimmunity.
Christensen
Sean R
SR
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Kashgarian
Michael
M
Alexopoulou
Lena
L
Flavell
Richard A
RA
Akira
Shizuo
S
Shlomchik
Mark J
MJ
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D000917:Antibody Formation / Q000276:immunology*; D001324:Autoantigens; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology; D004247:DNA / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D055517:snRNP Core Proteins
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D017411:Ribonucleoproteins, Small Nuclear; C495344:TLR3 protein, human; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051196:Toll-Like Receptor 3; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D055517:snRNP Core Proteins; D004247:DNA