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.
Subject(s)
Autoantigens/immunology , B-Lymphocytes/immunology , Lymphocyte Activation/immunology , Membrane Glycoproteins/physiology , RNA/metabolism , Receptors, Antigen, B-Cell/physiology , Toll-Like Receptor 7/physiology , Adaptor Proteins, Signal Transducing/deficiency , Adaptor Proteins, Signal Transducing/genetics , Animals , Antigens, Differentiation/genetics , Autoantibodies/biosynthesis , Autoantigens/metabolism , B-Lymphocytes/metabolism , Female , Hybridomas , Interferon-alpha/physiology , Lymphocyte Activation/genetics , Male , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Mice, Inbred C57BL , Mice, Inbred MRL lpr , Mice, Knockout , Mice, Transgenic , Myeloid Differentiation Factor 88 , Receptors, Antigen, B-Cell/genetics , Receptors, Immunologic/deficiency , Receptors, Immunologic/genetics , Ribonucleoproteins/immunology , Toll-Like Receptor 7/deficiency , Toll-Like Receptor 7/genetics , Toll-Like Receptor 9/deficiency , Toll-Like Receptor 9/genetics , Toll-Like Receptor 9/physiologyABSTRACT
Dendritic cell (DC) activation by nucleic acid-containing immunoglobulin (Ig)G complexes has been implicated in systemic lupus erythematosus (SLE) pathogenesis. However, the mechanisms responsible for activation and subsequent disease induction are not completely understood. Here we show that murine DCs are much more effectively activated by immune complexes that contain IgG bound to chromatin than by immune complexes that contain foreign protein. Activation by these chromatin immune complexes occurs by two distinct pathways. One pathway involves dual engagement of the Fc receptor FcgammaRIII and Toll-like receptor (TLR)9, whereas the other is TLR9 independent. Furthermore, there is a characteristic cytokine profile elicited by the chromatin immune complexes that distinguishes this response from that of conventional TLR ligands, notably the induction of BAFF and the lack of induction of interleukin 12. The data establish a critical role for self-antigen in DC activation and explain how the innate immune system might drive the adaptive immune response in SLE.