期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 202, 期 2, 页码 321-331出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20050338
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资金
- NIAID NIH HHS [P01 AI036529, P01AI36529, R01 AI061090] Funding Source: Medline
- NIAMS NIH HHS [P01 AR050256] Funding Source: Medline
- NIGMS NIH HHS [GM07205, T32 GM007205] Funding Source: Medline
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.
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