Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 2, Pages 407-417Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200523025
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Funding
- NCI NIH HHS [R01-CA69212, R01 CA069212] Funding Source: Medline
- NIAMS NIH HHS [T32 AR007258, 5T32AR07258] Funding Source: Medline
- NIDDK NIH HHS [P01 DK050305, P01-DK50305] Funding Source: Medline
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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 autoinumune 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.
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