Induction of Dendritic Cell Differentiation by IFN-α in Systemic Lupus Erythematosus

Blanco, Patrick; Palucka, A. Karolina; Gill, Michelle A.; Pascual, Virginia; Banchereau, Jacques

doi:10.1126/science.1064890

Cited by 1,175 publications

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“…Serum interferon (IFN)-α concentrations are elevated in patients with systemic lupus erythematosus (SLE) [1] and contribute to the break of peripheral tolerance by sustaining the differentiation of myeloid dendritic cells [2]. IFN-α actually increases the differentiation of monocytes into dendritic cells that present antigens from dying cells to CD4 + lymphocytes, resulting in their proliferation.…”

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confidence: 99%

“…Currently, PDCs activated by DNA- and RNA-containing immune complexes are believed to be the main source of IFN-α in SLE upon triggering of Toll-like receptor (TLR) 9 and TLR7, respectively, in cooperation with CD32 [6-8]. Nevertheless, PDC depletion experiments suggest that other cell types produce IFN-α in SLE [2] and type I IFN production occurs independently of Fcγ receptors in a lupus mouse model [9], indicating that uptake of immune complexes is not required. In a different lupus mouse model, the double-stranded RNA analog poly I:C was shown to induce IFN-α production in spleen monocytes [10], confirming that - depending on the stimulus - cells other than PDCs may produce IFN-α independently of the presence of immune complexes.…”

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confidence: 99%

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Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Decker

2011

Arthritis Res Ther

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Interferon-α plays a crucial role in the pathogenesis of systemic lupus erythematosus. Nevertheless, the different human cell types producing this cytokine as well as the stimuli inducing its production have not been completely characterized. So far, a subpopulation of dendritic cells activated by immune complexes has been identified as major producers of interferon-α in patients with lupus. However, those cells represent a minor population and some studies have reported the secretion of interferon-α by other cells. On the other hand, more than 50% of blood leukocytes are neutrophils and their functions are still not fully understood. Recent data suggest that neutrophils, though usually not considered interferon-α-producing cells, may represent an unexpected source of this cytokine in response to some lupus stimuli.

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Neutrophils and interferon-α-producing cells: who produces interferon in lupus?

Decker

2011

Arthritis Res Ther

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“…Second, a clearance deficiency of monocytes and macrophages causes accumulation of apoptotic bodies in different tissue types (20,21). Third, some monocytes become professional antigen-presenting cells upon stimulation with IFN␣ and may present processed antigens of ingested apoptotic cells and nucleosomes to CD4ϩ T cells that subsequently become activated (22).…”

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Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus

Biesen¹,

Demir²,

Barkhudarova³

et al. 2008

Arthritis & Rheumatism

175

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Objective. Type I interferon (IFN) plays a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE) and is therefore considered a potential therapeutic target. This study was undertaken to establish a feasible biomarker for IFN effects with respect to disease activity and effectiveness of IFN-suppressive therapy in SLE patients.Methods. Transcriptomes of purified monocytes from 9 SLE patients and 7 healthy controls were analyzed by Affymetrix GeneChip technology. Levels of sialic acid-binding Ig-like lectin 1 (Siglec-1) (sialoadhesin, CD169) in inflammatory and resident monocytes were determined at the protein level in 38 healthy controls and 52 SLE patients, using multicolor flow cytometry.Results. Transcriptomes of peripheral monocytes from SLE patients revealed a dominant type I IFN signature. Siglec-1 was identified as one of the most prominent type I IFN-regulated candidate genes. At the protein level, the frequency of Siglec-1-expressing monocyte subsets was correlated with disease activity (as measured by the SLE Disease Activity Index) and was inversely correlated with levels of complement factors. Most interestingly, levels of anti-doublestranded DNA (anti-dsDNA) antibodies were highly correlated with the percentage of resident monocytes, but not inflammatory monocytes, expressing Siglec-1. High-dose glucocorticoid treatment resulted in a dramatic reduction of Siglec-1 expression in cells from patients with active SLE.Conclusion. Our findings indicate that Siglec-1 expression in resident blood monocytes is a potential biomarker for monitoring disease activity, displaying type I IFN responses, and estimating levels of antidsDNA antibodies. Moreover, our results suggest that resident and inflammatory monocytes contribute differently to the process of autoantibody formation in SLE.

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“…We have previously shown that activation of the dendritic cell system in SLE patients occurs because of an unabated secretion of interferon-␣ (IFN␣) by plasmacytoid dendritic cells (10). In vitro studies also demonstrated that SLE dendritic cells have the unique capacity to activate CD8ϩ T lymphocytes, promoting their differentiation into effector-type cytotoxic T lymphocytes (11), whereas in vivo, there was an increased proportion of cytotoxic T lymphocytes, which correlated with scores on the SLE Disease Activity Index (SLEDAI) (12,13).…”

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confidence: 99%