RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement.
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.
Lau
Christina M
CM
Department of Microbiology, Boston University School of Medicine, MA 02118, USA.
Broughton
Courtney
C
Tabor
Abigail S
AS
Akira
Shizuo
S
Flavell
Richard A
RA
Mamula
Mark J
MJ
Christensen
Sean R
SR
Shlomchik
Mark J
MJ
Viglianti
Gregory A
GA
Rifkin
Ian R
IR
Marshak-Rothstein
Ann
A
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
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