Human lupus autoantibody–DNA complexes activate DCs through cooperation of CD32 and TLR9
Terry K. Means, … , Douglas T. Golenbock, Andrew D. Luster
Terry K. Means, … , Douglas T. Golenbock, Andrew D. Luster
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):407-417. https://doi.org/10.1172/JCI23025.
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Article Autoimmunity

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 FcγRIIa (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

Terry K. Means, Eicke Latz, Fumitaka Hayashi, Mandakolathur R. Murali, Douglas T. Golenbock, Andrew D. Luster

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ICs in SLE serum activate cytokine and chemokine production in human PDC...
ICs in SLE serum activate cytokine and chemokine production in human PDCs. (A) Normal human PDCs were isolated and stimulated at the indicated doses of purified non–SLE-ICs or SLE-ICs. After 8 hours of stimulation, the cells were harvested for RNA. (B) Normal human PDCs were stimulated with 100 ng/ml of non–SLE-ICs or SLE-ICs. Cells were harvested at the indicated time points for RNA. Expression of IL-8 and IFN-α was determined by QPCR and depicted as the number of copies of mRNA per copies of the control mRNA GAPDH. (C) Supernatants of the stimulated cells were collected after the cells were removed by centrifugation. ELISA was performed to detect human IL-8 and IFN-α at the 24-hour time point. Error bars indicate standard deviation of triplicate measurements. Expression of chemokines (D) and cytokines (E) was quantified by QPCR using total RNA isolated from PDCs (1 × 105 cells) stimulated with 100 ng/ml SLE-ICs for 1, 3, 8, 24, or 48 hours. Data are representative of 4 similar experiments conducted using 4 different donors.