Toll-like receptor 9-dependent and -independent dendritic cell activation by chromatin-immunoglobulin G complexes.
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.
Boulé
Melissa W
MW
Renal Section, Department of Medicine, Boston University School of Medicine, EBRC 5th Floor, 650 Albany Street, Boston, MA 02118, USA.
Broughton
Courtney
C
Mackay
Fabienne
F
Akira
Shizuo
S
Marshak-Rothstein
Ann
A
Rifkin
Ian R
IR
D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002417:Cattle; D002843:Chromatin / Q000276:immunology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology*; D007074:Immunoglobulin G / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018448:Models, Immunological; D009707:Nucleosomes / Q000276:immunology; D011956:Receptors, Cell Surface / Q000502:physiology*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D051217:Toll-Like Receptor 9
D002843:Chromatin; D017931:DNA Primers; D004268:DNA-Binding Proteins; C485700:Fcgr3 protein, mouse; D007074:Immunoglobulin G; D009707:Nucleosomes; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9