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C1q Inhibits Immune Complex-Induced Interferon-alpha Production in Plasmacytoid Dendritic Cells A Novel Link Between C1q Deficiency and Systemic Lupus Erythematosus Pathogenesis

Lood, Christian LU ; Gullstrand, Birgitta LU ; Truedsson, Lennart LU ; Olin, Anders LU ; Alm, Gunnar V.; Ronnblom, Lars; Sturfelt, Gunnar LU ; Eloranta, Maija-Leena and Bengtsson, Anders LU (2009) In Arthritis and Rheumatism 60(10). p.3081-3090
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 receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFN alpha). Methods. Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic... (More)
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 (IFN alpha). 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 alpha production was determined by an immunoassay. Results. C1q significantly inhibited PBMC IFN alpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFN alpha production induced by ICs and CpG DNA but increased PDC IFNa production induced by HSV. The regulatory role of C1q was not specific for IFN alpha 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. 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Arthritis and Rheumatism
volume
60
issue
10
pages
3081 - 3090
publisher
John Wiley & Sons
external identifiers
  • wos:000270696600026
  • pmid:19790049
  • scopus:70349769369
ISSN
1529-0131
DOI
10.1002/art.24852
language
English
LU publication?
yes
id
6dce3bdc-2405-4d6f-bf05-8924b8c9319d (old id 1507630)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19790049?dopt=Abstract
date added to LUP
2009-11-20 11:01:51
date last changed
2017-09-24 03:46:01
@article{6dce3bdc-2405-4d6f-bf05-8924b8c9319d,
  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 receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFN alpha). 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 alpha production was determined by an immunoassay. Results. C1q significantly inhibited PBMC IFN alpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFN alpha production induced by ICs and CpG DNA but increased PDC IFNa production induced by HSV. The regulatory role of C1q was not specific for IFN alpha 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. 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.},
  author       = {Lood, Christian and Gullstrand, Birgitta and Truedsson, Lennart and Olin, Anders and Alm, Gunnar V. and Ronnblom, Lars and Sturfelt, Gunnar and Eloranta, Maija-Leena and Bengtsson, Anders},
  issn         = {1529-0131},
  language     = {eng},
  number       = {10},
  pages        = {3081--3090},
  publisher    = {John Wiley & Sons},
  series       = {Arthritis and Rheumatism},
  title        = {C1q Inhibits Immune Complex-Induced Interferon-alpha Production in Plasmacytoid Dendritic Cells A Novel Link Between C1q Deficiency and Systemic Lupus Erythematosus Pathogenesis},
  url          = {http://dx.doi.org/10.1002/art.24852},
  volume       = {60},
  year         = {2009},
}