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

CM Lau, C Broughton, AS Tabor, S Akira… - The Journal of …, 2005 - rupress.org
CM Lau, C Broughton, AS Tabor, S Akira, RA Flavell, MJ Mamula, SR Christensen
The Journal of experimental medicine, 2005rupress.org
Previous studies (Leadbetter, EA, IR Rifkin, AH Hohlbaum, B. Beaudette, MJ Shlomchik, and
A. Marshak-Rothstein. 2002. Nature. 416: 603–607; Viglianti, GA, CM Lau, TM Hanley, BA
Miko, MJ 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 …
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.
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