Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathogenic autoantibodies against nucleoproteins and DNA. Here we show that DNA-containing immune complexes (ICs) within lupus serum (SLE-ICs), but not protein-containing ICs from other autoimmune rheumatic diseases, stimulates plasmacytoid DCs (PDCs) to produce cytokines and chemokines via a cooperative interaction between Toll-like receptor 9 (TLR9) and FcgammaRIIa (CD32). SLE-ICs transiently colocalized to a subcellular compartment containing CD32 and TLR9, and CD32+, but not CD32-, PDCs internalized and responded to SLE-ICs. Our findings demonstrate a novel functional interaction between Fc receptors and TLRs, defining a pathway in which CD32 delivers SLE-ICs to intracellular lysosomes containing TLR9, inducing a signaling cascade leading to PDC activation. These data demonstrate that endogenous DNA-containing autoantibody complexes found in the serum of patients with SLE activate the innate immune system and suggest a novel mechanism whereby these ICs contribute to the pathogenesis of this autoimmune disease.
Means
Terry K
TK
Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.
Latz
Eicke
E
Hayashi
Fumitaka
F
Murali
Mandakolathur R
MR
Golenbock
Douglas T
DT
Luster
Andrew D
AD
D000974:Antibodies, Antinuclear / Q000276:immunology*; D000936:Antigen-Antibody Complex / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors