C1q inhibits immune complex–induced interferon‐α production in plasmacytoid dendritic cells: A novel link between C1q deficiency and systemic lupus erythematosus pathogenesis

Abstract

Objective. C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll-like receptorinduced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-␣ (IFN␣). Methods.Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFN␣ production was determined by an immunoassay.Results. C1q significantly inhibited PBMC IFN␣ production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFN␣ production induced by ICs and CpG DNA but increased PDC IFN␣ production induced by HSV. The regulatory role of C1q was not specific for IFN␣ but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor ␣. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins.Conclusion. Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up-regulation of the type I IFN system seen in SLE patients.Systemic lupus erythematosus (SLE) is a systemic autoimmune disease involving several organ systems, and it is also characterized by the presence of B cell hyperreactivity, autoantibodies, increased complement consumption, and an ongoing production of type I interferon (IFN) (1). The elevated serum levels of IFN␣ in SLE patients have been proposed to have a significant role in the pathogenesis of SLE. Administration of recombinant IFN␣ to patients with viral infections or malignancies can lead to the development of antinuclear antibodies as well as to SLE or other autoimmune

Annexin A2 and A5 Serve as New Ligands for C1q on Apoptotic Cells

“…To support this, evidence has been presented supporting the role of C1q in development of tolerance (46), clearance of immune complexes (47), and cytokine regulation (48). It differentially modulates the phagocytosis and cytokine responses during ingestion of apoptotic cells by human monocytes, macrophages, and dendritic cells as well as of apoptotic neurons by microglia (49,50).…”

Molecular Mechanisms for Synchronized Transcription of Three Complement C1q Subunit Genes in Dendritic Cells and Macrophages

“…Although genetic C1q deficiency is rare, acquired C1q deficiency is more frequently found in SLE patients, which could contribute to SLE pathogenesis. For example, increased IFN␣ production by plasmacytoid DCs could result from reduced C1q levels (39). The reduced C1q levels could attribute partly to inflammatory consumption and anti-C1q autoantibodies (27,28).…”

IgG glycan hydrolysis by endoglycosidase S diminishes the proinflammatory properties of immune complexes from patients with systemic lupus erythematosus: A possible new treatment?

“…In order to investigate whether EndoS inhibited IC-induced IFN␣ production by PDCs, we cultured PDCs at a final concentration of 2 ϫ 10 5 cells/ml in 100 l of Macrophage-SFM medium containing 20 mM HEPES, 50 g/ml gentamicin, 2 ng/ml granulocytemacrophage colony-stimulating factor (Leukine; Berlex), and 500 units/ml Intron A (SP Company), stimulated with anti-RNP antibodies and necrotic material as described previously (28), and incubated for 20 hours at 37°C with 5% CO 2 and 97% humidity. Briefly, anti-RNP-positive sera were pooled, and IgG was purified on a protein G column (Protein G Superose HR 10/2; Pharmacia LKB).…”

“…IgG purified from SLE serum at a concentration of 0.25 mg/ml was mixed with necrotic material from Jurkat cell supernatant at a concentration of 5% volume/volume to form RNA-containing ICs. These ICs have been characterized in previous studies to contain RNA and induce high amounts of IFN␣ through Fc␥RIIA and Toll-like receptor 7 in PDCs (28)(29)(30). For some experiments, EndoS-treated anti-RNP antibodies were used.…”

“…For the kinetics assay, EndoS was added at a concentration of 0.25 mg/ml together with PBMCs and ICs at different time points. The amount of IFN␣ produced was determined by dissociationenhanced lanthanide fluoroimmunoassay using the LT 27:293 and 297EU antibodies as previously described (28).…”