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Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP-C1q interaction
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Rheumatology in Östergötland.
Linköping University, Department of Clinical and Experimental Medicine, Rheumatology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0002-6916-5490
Linköping University, Department of Medical and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
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2007 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 1, 251-258 p.Article in journal (Refereed) Published
Abstract [en]

C-reactive protein (CRP) interacts with phosphorylcholine (PC), Fcγ receptors, complement factor C1q and cell nuclear constituents, yet its biological roles are insufficiently understood. The aim was to characterize CRP-induced complement activation by ellipsometry. PC conjugated with keyhole limpet hemocyanin (PC-KLH) was immobilized to cross-linked fibrinogen. A low-CRP serum with different amounts of added CRP was exposed to the PC-surfaces. The total serum protein deposition was quantified and deposition of IgG, C1q, C3c, C4, factor H, and CRP detected with polyclonal antibodies. The binding of serum CRP to PC-KLH dose-dependently triggered activation of the classical pathway. Unexpectedly, the activation was efficiently down-regulated at CRP levels >150 mg/L. Using radial immunodiffusion, CRP–C1q interaction was observed in serum samples with high CRP concentrations. We propose that the underlying mechanism depends on fluid-phase interaction between C1q and CRP. This might constitute another level of complement regulation, which has implications for systemic lupus erythematosus where CRP is often low despite flare-ups.

Place, publisher, year, edition, pages
2007. Vol. 352, no 1, 251-258 p.
Keyword [en]
C-reactive protein, C1q, Complement, Inflammation, Opsonization, Pentraxins, Systemic lupus erythematosus
National Category
Natural Sciences
URN: urn:nbn:se:liu:diva-13891DOI: 10.1016/j.bbrc.2006.11.013OAI: diva2:22135
Available from: 2006-07-10 Created: 2006-07-10 Last updated: 2015-08-31
In thesis
1. C-reactive protein (CRP) and anti-CRP autoantibodies in systemic lupus erythematosus: a study on the occurrence and clinical implications of anti-CRP antibodies and CRP-mediated complement activation
Open this publication in new window or tab >>C-reactive protein (CRP) and anti-CRP autoantibodies in systemic lupus erythematosus: a study on the occurrence and clinical implications of anti-CRP antibodies and CRP-mediated complement activation
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by production of a wide range of autoantibodies, multiple organ involvement and by local formation or tissue deposition of immune complexes (ICs) in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologs in vertebrates and several invertebrates. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc receptors and activates the complement system via C1q.

The aims of this thesis were to investigate the complement activation properties of CRP; to elucidate if anti-CRP antibodies occur in SLE and, if so, whether anti-CRP antibody levels correlate with disease activity in SLE; to test the hypothesis that autoantibodies to pro-inflammatory cytokines prevent rise of CRP; and to survey if autoantibodies to certain nuclear antigens or to CRP correlate with cytokine-inducing properties of ICs from SLE sera.

We have demonstrated that CRP bound to phosphorylcholine is a powerful activator of the classical complement pathway already in the CRP concentration range 4 to 10 mg/L, but with a marked inhibition at CRP levels above 150 mg/L. Autoantibodies to the monomeric form of CRP were found in approximately 40 percent of SLE patients and in a few sera from patients with primary Sjögren’s syndrome, but not in rheumatoid arthritis or in inflammatory bowel disease. The anti-CRP antibody levels showed significant correlations to several laboratory and clinical measurements, and anti-CRP positivity was associated with renal involvement in SLE. Native CRP levels were not correlated with anti-CRP or anti-cytokine antibody levels. Hence, the presence of antibodies to monomeric CRP or to CRP-inducing cytokines is an unlikely explanation to the relative failure of CRP response in patients with active lupus. However, antibodies to TNFα were found in subnormal levels at disease flares, whereas antibodies to TGFβ were found in supranormal levels as compared to healthy subjects. In contrast to antibodies against CRP and DNA, anti-SSA and anti-SSB antibodies may regulate the inflammatory process in SLE by enhancing IC formation and subsequent production of cytokines such as IL-6, IL-10 and IL-12p40. Hypothetically, anti-CRP autoantibodies may be of pathogenic importance, for instance by binding to monomeric CRP on cell and tissue surfaces and thereby increasing the risk of extrahepatic deposition of apoptotic material and in situ formation of ICs.

Place, publisher, year, edition, pages
Institutionen för molekylär och klinisk medicin, 2006
Linköping University Medical Dissertations, ISSN 0345-0082 ; 931
autoantibodies, complement activation, C-reactive protein, cytokines, immune complex, immunoregulation, opsonization, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
urn:nbn:se:liu:diva-7067 (URN)91-85497-66-5 (ISBN)
Public defence
2006-01-20, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (English)
On the day of the defence data the status of article I was Submitted and the tile was "C-reactive protein activates or inhibits the classical complement pathway in a concentration dependent manner" and the status of article V was: Submitted.Available from: 2006-07-10 Created: 2006-07-10 Last updated: 2015-08-31

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Sjöwall, ChristofferWetterö, JonasBengtsson, TorbjörnAskendal, AgnetaSkogh, ThomasTengvall, Pentti
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