C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis.
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 receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFNalpha).


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. IFNalpha production was determined by an immunoassay.


RESULTS
C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFNalpha production induced by ICs and CpG DNA but increased PDC IFNalpha production induced by HSV. The regulatory role of C1q was not specific for IFNalpha but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha. 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.


CONCLUSIONS
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.
Lood
Christian
C
Lund University Hospital and Lund University, Lund, Sweden.
Gullstrand
Birgitta
B
Truedsson
Lennart
L
Olin
Anders I
AI
Alm
Gunnar V
GV
Rönnblom
Lars
L
Sturfelt
Gunnar
G
Eloranta
Maija-Leena
ML
Bengtsson
Anders A
AA
D000936:Antigen-Antibody Complex / Q000378:metabolism*; D002478:Cells, Cultured; D015922:Complement C1q / Q000172:deficiency / Q000378:metabolism*; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism; D016898:Interferon-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000209:etiology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D011951:Receptors, Complement / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000378:metabolism; D012307:Risk Factors; D018139:Simplexvirus / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000936:Antigen-Antibody Complex; D039421:Integrin alpha2; D016898:Interferon-alpha; D015850:Interleukin-6; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D014409:Tumor Necrosis Factor-alpha; C032402:complement 1q receptor; D015922:Complement C1q