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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-, 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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