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

J Exp Med. 2005 Nov 7;202(9):1171-7. doi: 10.1084/jem.20050630. Epub 2005 Oct 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Antigens, Differentiation / genetics
  • Autoantibodies / biosynthesis
  • Autoantigens / immunology*
  • Autoantigens / metabolism
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Female
  • Hybridomas
  • Interferon-alpha / physiology
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Male
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Mice, Transgenic
  • Myeloid Differentiation Factor 88
  • RNA / metabolism*
  • Receptors, Antigen, B-Cell / genetics
  • Receptors, Antigen, B-Cell / physiology*
  • Receptors, Immunologic / deficiency
  • Receptors, Immunologic / genetics
  • Ribonucleoproteins / immunology
  • Toll-Like Receptor 7 / deficiency
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / physiology*
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / genetics
  • Toll-Like Receptor 9 / physiology

Substances

  • Adaptor Proteins, Signal Transducing
  • Antigens, Differentiation
  • Autoantibodies
  • Autoantigens
  • Interferon-alpha
  • Membrane Glycoproteins
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Receptors, Antigen, B-Cell
  • Receptors, Immunologic
  • Ribonucleoproteins
  • Tlr7 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • RNA