RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement

By Christina M. Lau, C. Broughton, Abigail S. Tabor, Shizuo Akira, R. Flavell, M. Mamula, S. Christensen, M. Shlomchik, G. Viglianti, I. Rifkin and 1 more. Journal of Experimental Medicine, 2005

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Previous studies (Leadbetter, E.A., I.R. Rifkin, A.H. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Nature. 416:603–607; Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Shlomchik, and A. Marshak-Rothstein. 2003. Immunity. 19:837–847) established the unique capacity of DNA and DNA-associated autoantigens to activate autoreactive B cells via sequential engagement of the B cell antigen receptor (BCR) and Toll-like receptor (TLR) 9. We demonstrate that this two-receptor paradigm can be extended to the BCR/TLR7 activation of autoreactive B cells by RNA and RNA-associated autoantigens. These data implicate TLR recognition of endogenous ligands in the response to both DNA- and RNA-associated autoantigens. Importantly, the response to RNA-associated autoantigens was markedly enhanced by IFN-α, a cytokine strongly linked to disease progression in patients with systemic lupus erythematosus (SLE). As further evidence that TLRs play a key role in autoantibody responses in SLE, we found that autoimmune-prone mice, lacking the TLR adaptor protein MyD88, had markedly reduced chromatin, Sm, and rheumatoid factor autoantibody titers.

Subfields: Immunology, Rheumatology

View Paper: https://www.semanticscholar.org/paper/042f53aa8bfeb887a6351aa9a572b544dbeca899

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In Immunology

In Rheumatology

Shizuo Akira

Citations in the corpus

Intracellular toll-like receptors. (2010, background): “uptake of proteins complexed to nucleic acids (Lau et al., 2005; Leadbetter et al., 2002).”
Identification of a key pathway required for the sterile inflammatory response triggered by dying cells (2007, background): “There is evidence that some mammalian cellular components can stimulate TLR”
Type I interferon in systemic lupus erythematosus and other autoimmune diseases. (2006, background): “As shown for pDCs, immune complexes containing RNA and RNA-associated autoantigens activate autoreactive B cells in vitro (Lau et al., 2005).”
DAMPening Inflammation by Modulating TLR Signalling (2010, background): “Finally, B cells are activated by DNAor RNA-associated autoantigens by combined B cell antigen receptor (BCR)/TLR9 or TLR7 engagement [93, 94].”
Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. (2006, background): “Since all classes of nuclear Abs were absent in MyD88-deficient autoimmune-prone mice, however, it *Correspondence: mark.shlomchik@yale.edu seems likely that anti-Sm and other RNA Abs are controlled by another TLR ( Lau et al., 2005 ).”
Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses (2009, background): “Binding of the immune complex by the BCR, or by the Fc R in the case of pDCs, is followed by BCR-mediated endocytosis and delivery of the immune complex to an endosomal compartment, which allows ssRNA and CpG DNA motifs within the autoantigen to activate the cell through TLR7 and TLR9, respectively ”