title: Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.
abstract: 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.
authors.affiliation: Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Hayashi
authors.forename: Mandakolathur R
authors.initials: MR
authors.lastname: Murali
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
mesh_terms: 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
chemical_list: 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