Toll-like Receptor 7 and TLR9 Dictate Autoantibody Specificity and Have Opposing Inflammatory and Regulatory Roles in a Murine Model of Lupus
Open accessAbstract
Antibodies (Abs) to RNA- and DNA-containing autoantigens are characteristic of systemic lupus erythematosus (SLE). We showed previously that Toll-like receptor (TLR) 9, recognizing DNA, is required for the spontaneous generation of DNA autoantibodies, but not for the development of lupus nephritis in susceptible mice. We report that lupus-prone mice deficient in TLR7, a receptor for ssRNA, failed to generate Abs to RNA-containing antigens (Ags) such as Smith (Sm) Ag. TLR9 and TLR7 also had dramatic effects on clinical disease in lupus-prone mice. In the absence of TLR9, autoimmune disease was exacerbated, lymphocytes and plasmacytoid DCs were more activated, and serum IgG and IFN-alpha were increased. In contrast, TLR7-deficient mice had ameliorated disease, decreased lymphocyte activation, and decreased serum IgG. These findings reveal opposing inflammatory and regulatory roles for TLR7 and TLR9, despite similar tissue expression and signaling pathways. These results have important implications for TLR-directed therapy of autoimmune disease.
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SLE has been linked to TLR9 overstimulation by self DNA.
“MAS is recognized also as a complication of systemic lupus erythematosus (34), a disease that has been linked to TLR9 overstimulation by self DNA (35)(36)(37)(38).”
From Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice (2011) · cites this paper as [36]
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- Authors
- Christensen, S. R., Shupe, J., Nickerson, K., Kashgarian, M., Flavell, R. A., & Shlomchik, M. J.
- Affiliations
- Yale University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shlomchik, Mark J.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2006-09
- Volume
- 25
- Issue
- 3
- Pages
- 417-428
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2134106169
- Cited by
- 1,090
- References
- 50
- Citations by year
- 2026: 36 · 2025: 36 · 2024: 47 · 2023: 42 · 2022: 45 · 2021: 45 · 2020: 45 · 2019: 52 · 2018: 54 · 2017: 47 · 2016: 50 · 2015: 68 · 2014: 49 · 2013: 81 · 2012: 58
- FWCI
- 44.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Yale University
- National Institutes of Health
- National Institute of General Medical Sciences (GM07205, T32GM007205)
- National Institute of Allergy and Infectious Diseases (P01AI036529)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P01AR050256)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TLR7, TLR9, systemic lupus erythematosus, autoantibody specificity, lupus-prone mice, lupus nephritis, plasmacytoid dendritic cells, lymphocyte activation, interferon-alpha, serum IgG, autoimmunity regulation
- MeSH terms
- Animals, Antibody Specificity, Autoantibodies, Cells, Cultured, Female, Humans, Immunoglobulin G, Lupus Erythematosus, Systemic, Lymphocyte Activation, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Inbred MRL lpr, Toll-Like Receptor 7, Toll-Like Receptor 9, Mice
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