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¹ Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
² Department of Pathology, Yale University School of Medicine, New Haven, CT 06510
³ Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510
⁴ Centre d'Immunologie de Marseille-Luminy, INSERM-CNRS, University of Mediterranee, Campus de Luminy, 13288 Marseille Cedex 09, France
⁵ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita City, Osaka 565-0871, Japan
⁶ Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan

CORRESPONDENCE Mark J. Shlomchik: mark.shlomchik{at}yale.edu

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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