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Published online 31 October 2005 doi:10.1084/jem.20050630
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 9, 1171-1177
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BRIEF DEFINITIVE REPORT

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

Christina M. Lau1, Courtney Broughton2, Abigail S. Tabor1, Shizuo Akira3, Richard A. Flavell4, Mark J. Mamula5, Sean R. Christensen4,6, Mark J. Shlomchik4,6, Gregory A. Viglianti1, Ian R. Rifkin2, and Ann Marshak-Rothstein1

1 Department of Microbiology, Boston University School of Medicine, Boston, MA 02118
2 Department of Medicine, Boston University School of Medicine, Boston, MA 02118
3 Research Institute for Microbial Diseases, Osaka University, Suita-ku, Osaka 565-0871, Japan
4 Section of Immunobiology, Department of Internal Medicine
5 Section of Rheumatology, Department of Internal Medicine
6 Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06510

CORRESPONDENCE Ann Marshak-Rothstein: amrothst{at}bu.edu

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-{alpha}, 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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