title: RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement.
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.
authors.affiliation: Department of Microbiology, Boston University School of Medicine, MA 02118, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lau
authors.forename: Courtney
authors.initials: C
authors.lastname: Broughton
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Tabor
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Mamula
authors.forename: Sean R
authors.initials: SR
authors.lastname: Christensen
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Shlomchik
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Viglianti
authors.forename: Ian R
authors.initials: IR
authors.lastname: Rifkin
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006825:Hybridomas; D016898:Interferon-alpha / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88; D012313:RNA / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000502:physiology*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics; D012261:Ribonucleoproteins / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D001323:Autoantibodies; D001324:Autoantigens; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011947:Receptors, Antigen, B-Cell; D011971:Receptors, Immunologic; D012261:Ribonucleoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D012313:RNA