Plasmacytoid Dendritic Cells and C1q Differentially Regulate Inflammatory Gene Induction by Lupus Immune Complexes

ObjectivesPatients with systemic lupus erythematosus (SLE) have an ongoing interferon-α (IFN-α) production by plasmacytoid dendritic cells (pDCs). We investigated whether T cells can promote IFN-α production by pDCs.MethodsHuman pDCs were stimulated with immune complexes (ICs) containing U1 small nuclear ribonucleic proteins particles and SLE-IgG (RNA-IC) in the presence of T cells or T cell supernatants. T cells were activated by anti-CD3/CD28 antibodies or in a mixed leucocyte reaction. IFN-α and other cytokines were determined in culture supernatants or patient sera with immunoassays. The effect of interleukin (IL) 3 and granulocyte-macrophage-colony-stimulating factor (GM-CSF) on pDCs was examined by the use of antibodies, and the expression of CD80/CD86 was determined using flow cytometry.ResultsActivated T cells and supernatants from activated T cells increased IFN-α production by >20-fold. The stimulatory effect of T cell supernatants was reduced after depletion of GM-CSF (81%) or by blocking the GM-CSF receptor (55%–81%). Supernatant from activated T cells, furthermore, increased the frequency of CD80 and CD86 expressing pDCs stimulated with RNA-IC from 6% to 35% (p<0.05) and from 10% to 26% (p<0.01), respectively. Activated SLE T cells enhanced IFN-α production to the same extent as T cells from healthy individuals and a subset of patients with SLE had increased serum levels of GM-CSF.ConclusionsActivated T cells enhance IFN-α production by RNA-IC stimulated pDCs via GM-CSF and induce pDC maturation. Given the increased serum levels of GM-CSF in a subset of patients with SLE, these findings suggest that activated T cells may upregulate type I IFN production in SLE.

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U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7

Blood ◽

10.1182/blood-2005-07-2650 ◽

2006 ◽

Vol 107 (8) ◽

pp. 3229-3234 ◽

Cited By ~ 188

Author(s):

Emina Savarese ◽

Ohk-wha Chae ◽

Simon Trowitzsch ◽

Gert Weber ◽

Berthold Kastner ◽

...

Keyword(s):

Dendritic Cells ◽

Lupus Erythematosus ◽

Immune Complexes ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Dependent Manner ◽

Stem Loop ◽

Murine Bone Marrow ◽

Small Nuclear Ribonucleoprotein ◽

Nuclear Antigens

Abstract Plasmacytoid dendritic cells (PDCs), which produce IFN-α in response to autoimmune complexes containing nuclear antigens, are thought to be critically involved in the pathogenesis of systemic lupus erythematosus (SLE). One of the immunostimulatory components of SLE immune complexes (SLE-ICs) is self DNA, which is recognized through Tlr9 in PDCs and B cells. Small nuclear ribonucleoproteins (snRNPs) are another major component of SLE-ICs in 30% to 40% of patients. In this study, we show that murine PDCs are activated by purified U1snRNP/anti-Sm ICs to produce IFN-α and proinflammatory cytokines and to up-regulate costimulatory molecules. The induction of IFN-α and IL-6 by U1snRNPs in murine bone marrow–derived PDCs required the presence of intact U1RNA and was largely dependent on Tlr7 but independent of Tlr3. Intracellularly delivered isolated U1snRNA and oligoribonucleotides derived from the stem loop regions and the Sm-binding site of U1snRNA efficiently induced IFN-α and IL-6 in Flt3L-cultured DCs in a Tlr7-dependent manner. The U1snRNA component of U1snRNP immune complexes, found in patients with SLE, acts as an endogenous “self” ligand for Tlr7 and triggers IFN-α and IL-6 production in PDCs.

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