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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.

SUBMITTER: Means TK

PROVIDER: S-EPMC544604 | biostudies-literature | 2005 Feb

REPOSITORIES: biostudies-literature

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Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.

Means Terry K TK Latz Eicke E Hayashi Fumitaka F Murali Mandakolathur R MR Golenbock Douglas T DT Luster Andrew D AD

The Journal of clinical investigation 20050201 2

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 subcellu ...[more]

PMID: 15668740

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Project description:ObjectiveNaturally arising IgM antibodies (NAb) to apoptotic cell (AC) determinants are present from birth and can be further induced by AC challenge. In systemic lupus erythematosus, lower anti-AC NAb levels have been associated with higher disease activity. We have recently shown that a prototypical AC-specific IgM NAb can suppress proinflammatory responses to purified agonists of Toll-like receptors and block the in vivo induction of IgG immune complex (IC)-induced arthritis. Nuclear antigens, which activate dendritic cells (DCs), form complexes with IgG autoantibody, and these have been implicated in the pathogenesis of autoimmune disease. In this study, we sought to investigate potential roles of such NAb for regulating IC-mediated activation of DCs, which is believed to be involved in disease initiation and perpetuation.MethodsBone marrow-derived myeloid DCs were stimulated with ICs composed of IgG autoantibody and chromatin or IgG autoantibody and RNA. Outcome was evaluated according to the production of inflammatory cytokines, as determined by enzyme-linked immunosorbent assay, and the expression of costimulatory molecules (markers of DC activation), as determined by flow cytometry. MAPK activation was evaluated by phospho-flow analysis and immunofluorescence microscopy.ResultsIgM anti-AC NAb dose-dependently suppressed the production of DNA IC- and RNA IC-induced interleukin-6 and DNA IC-induced tumor necrosis factor α, as well as the RNA IC-induced up-regulation of CD86 and CD40 on DCs. IgM NAb-mediated inhibition was associated with suppression of IC-mediated p38 MAPK activation and nuclear localization.ConclusionWe demonstrated a direct in vitro inhibitory effect of IgM NAb on inflammatory responses induced by IgG-nucleic acid ICs. These findings contribute to emerging evidence that regulatory NAb to AC determinants may oppose the influence of pathogenic lupus autoantibody ICs and thereby play roles in the maintenance of immune homeostasis.

Dataset Information

Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.

Publications

Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9.

Similar Datasets

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