Regulation of autoreactive B cell responses to endogenous TLR ligands
Open accessAbstract
Immune complexes containing DNA and RNA are responsible for disease manifestations found in patients with systemic lupus erythematosus (SLE). B cells contribute to SLE pathology through BCR recognition of endogenous DNA- and RNA- associated autoantigens and delivery of these self-constituents to endosomal TLR9 and TLR7, respectively. B cell activation by these pathways leads to production of class-switched DNA- and RNA-reactive autoantibodies, contributing to an inflammatory amplification loop characteristic of disease. Intriguingly, self-DNA and RNA are typically non-stimulatory for TLR9/7 due to the absence of stimulatory sequences or the presence of molecular modifications. Recent evidence from our laboratory and others suggests that B cell activation by BCR/TLR pathways is tightly regulated by surface-expressed receptors on B cells, and the outcome of activation depends on the balance of stimulatory and inhibitory signals. Either IFNalpha engagement of the type I IFN receptor or loss of IgG ligation of the inhibitory FcgammaRIIB receptor promotes B cell activation by weakly stimulatory DNA and RNA TLR ligands. In this context, autoreactive B cells can respond robustly to common autoantigens. These findings have important implications for the role of B cells in vivo in the pathology of SLE.
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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 [35]
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- [28]Lau CM Broughton C Tabor AS Akira S Flavell RA Mamula MJ Christensen SR Shlomchik MJ Viglianti GA Rifkin IR RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement J Exp Med 2005 202 1171 7 16260486 PMC2213226
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Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice
Behrens, E. M., Canna, S. W., Slade, K., Rao, S., Kreiger, P. A., Paessler, M., Kambayashi, T., & Koretzky, G. A. (2011) · Journal of Clinical Investigation · doi:10.1172/jci43157 · Cited by 392 · see citing works
- Authors
- Avalos, A. M., Busconi, L., & Marshak-Rothstein, A.
- Affiliations
- Boston University (US)
- Venue
- Autoimmunity
- Publisher
- Informa UK Limited
- Published
- 2009-12-17
- Volume
- 43
- Issue
- 1
- Pages
- 76-83
- ISSN
- 0891-6934 (ISSN-L)
- 1607-842X
- PMC
- PMC3059585
- OpenAlex
- W2135884655
- Cited by
- 114
- References
- 64
- Citations by year
- 2026: 3 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 6 · 2018: 4 · 2017: 8 · 2016: 7 · 2015: 14 · 2014: 10 · 2013: 7 · 2012: 18
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Autoimmunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR035230, 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
- systemic lupus erythematosus, autoreactive B cells, B cell activation, TLR9, TLR7, self-DNA, immune complexes, B cell receptor signaling, type I interferon receptor, interferon-alpha, Fc gamma receptor IIb, autoantibodies, class switch recombination, autoantigens
- MeSH terms
- Animals, Autoantigens, B-Lymphocytes, Disease Models, Animal, Humans, Immunity, Innate, Lupus Erythematosus, Systemic, Lymphocyte Activation, Toll-Like Receptor 7, Toll-Like Receptor 9
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