Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus.

Abstract

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.

• Authors: Sean R Christensen, Michael Kashgarian, Lena Alexopoulou, Richard A Flavell, Shizuo Akira, Mark J Shlomchik
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 202 Issue 2 Pg. 321-31 (Jul 18 2005) ISSN: 0022-1007 [Print] United States
• PMID: 16027240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Antinuclear
• Autoantigens
• DNA-Binding Proteins
• Membrane Glycoproteins
• Receptors, Cell Surface
• Ribonucleoproteins, Small Nuclear
• TLR3 protein, human
• TLR9 protein, human
• Tlr9 protein, mouse
• Toll-Like Receptor 3
• Toll-Like Receptor 9
• Toll-Like Receptors
• snRNP Core Proteins
• DNA

Topics

• Animals
• Antibodies, Antinuclear (immunology)
• Antibody Formation (immunology)
• Autoantigens
• Autoimmunity
• B-Lymphocytes (immunology)
• DNA (immunology)
• DNA-Binding Proteins (genetics, immunology)
• Humans
• Immunity, Innate
• Lupus Nephritis (genetics, immunology, pathology)
• Membrane Glycoproteins (genetics, immunology)
• Mice
• Mice, Knockout
• Receptors, Cell Surface (genetics, immunology)
• Ribonucleoproteins, Small Nuclear (immunology)
• Toll-Like Receptor 3
• Toll-Like Receptor 9
• Toll-Like Receptors
• snRNP Core Proteins