| 1. |
- Enocsson, Helena, et al.
(författare)
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Interferon-alpha Mediates Suppression of C-Reactive Protein Explanation for Muted C-Reactive Protein Response in Lupus Flares?
- 2009
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Ingår i: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 60:12, s. 3755-3760
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Tidskriftsartikel (refereegranskat)abstract
- Objective. C-reactive protein (CRP) is synthesized by hepatocytes in response to interleukin-6 (IL-6) during inflammation. Despite raised IL-6 levels and extensive systemic inflammation, serum CRP levels remain low during most viral infections and disease flares of systemic lupus erythematosus (SLE). Because both viral infections and SLE are characterized by high levels of interferon-alpha (IFN alpha), the aim of this study was to determine whether this cytokine can inhibit the induction of CRP. Methods. The interference of all 12 IFN alpha subtypes with CRP promoter activity induced by IL-6 and IL-1 beta was studied in a CRP promoter- and luciferase reporter-transfected human hepatoma cell line, Hep-G2. CRIP secretion by primary human hepatocytes was analyzed by enzyme-linked immunosorbent assay. Results. CRP promoter activity was inhibited by all single IFN alpha subtypes, as well as by 2 different mixtures of biologically relevant IFN alpha subtypes. The most prominent effect was seen using a leukocyte-produced mixture of IFN alpha (56% inhibition at 1,000 IU/ml). The inhibitory effect of IFN alpha was confirmed in primary human hepatocytes. CRP promoter inhibition was dose dependent and mediated via the type I IFN receptor. Transferrin production and Hep-G2 proliferation/viability were not affected by IFN alpha. Conclusion. The current study demonstrates that IFN alpha is an inhibitor of CRP promoter activity and CRP secretion. This finding concords with previous observations of up-regulated IFN alpha and a muted CRP response during SLE disease flares. Given the fundamental role of both IFN alpha and CRP in the immune response, our results are of importance for understanding the pathogenesis of SLE and may also contribute to understanding the differences in the CRP response between viral and bacterial infections.
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| 2. |
- Mathsson, Linda, et al.
(författare)
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Cytokine induction by circulating immune complexes and signs of in-vivo complement activation in systemic lupus erythematosus are associated with the occurrence of anti-Sjögren's syndrome A antibodies
- 2007
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 147:3, s. 513-520
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Tidskriftsartikel (refereegranskat)abstract
- Circulating immune complexes (IC) and levels of IC-induced cytokines have been correlated with complement activation and autoantibody profiles in systemic lupus erythematosus (SLE). SLE sera were analysed concerning levels of immune complexes (IC), classical complement function and different antinuclear and anti-C-reactive protein (CRP) autoantibodies. Blood mononuclear cells from healthy donors were stimulated with isolated IC and production of interleukin (IL)-10, IL-6 and IL-12p40 was measured. Functional experiments revealed that increased levels of IC-induced cytokines were associated with both increased classical complement activation and the occurrence of anti-Sjögren's syndrome A (SSA) and anti-SSB but not other autoantibodies. Biochemical measurement of circulating IC showed that the degree of complement activation and the occurrence of anti-SSA were synergistically associated with levels of circulating IC in SLE sera, as complement activation was a prerequisite for the enhancing effect of anti-SSA. Anti-CRP was associated with complement activation, but not with other autoantibodies. Our results indicate that anti-SSA and possibly anti-SSB antibodies influence IC formation and subsequent IC-induced cytokine induction, and that they thereby participate in the inflammatory process in active SLE.
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| 3. |
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| 6. |
- Sjöwall, Christoffer, 1975-, et al.
(författare)
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Pathogenic implications for autoantibodies against C-reactive protein and other acute phase proteins
- 2007
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Ingår i: Clinica Chimica Acta. - : Elsevier BV. - 0009-8981 .- 1873-3492. ; 378:1-2, s. 13-23
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a systemic rheumatic disease characterized clinically by multiorgan involvement and serologically by the occurrence of antinuclear antibodies. SLE patients may present with multiple autoantibodies to cytoplasmic and cell surface antigens as well as to circulating plasma proteins. Another feature of SLE is that serum levels of C-reactive protein (CRP) often remain low despite high disease activity and despite high levels of other acute phase proteins and interleukin-6, i.e. the main CRP inducing cytokine. Apart from its important role as a laboratory marker of inflammation, CRP attracts increasing interest due to its many intriguing biological functions, one of which is a role as an opsonin contributing to the elimination of apoptotic cell debris, e.g. nucleosomes, thereby preventing immunization against autoantigens. Recently, autoantibodies against CRP and other acute phase proteins have been reported in certain rheumatic conditions, including SLE. Although the presence of anti-CRP autoantibodies does not explain the failed CRP response in SLE, antibodies directed against acute phase proteins have several implications of pathogenetic interest. This paper thus highlights the biological and clinical aspects of native and monomeric CRP and anti-CRP, as well as autoantibodies against mannose-binding lectin, serum amyloid A and serum amyloid P component. © 2006 Elsevier B.V. All rights reserved.
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| 7. |
- Sjöwall, Christoffer, et al.
(författare)
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Solid-phase classical complement activation by C-reactive protein (CRP) is inhibited by fluid-phase CRP-C1q interaction.
- 2007
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Ingår i: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 352:1, s. 251-8
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Tidskriftsartikel (refereegranskat)abstract
- C-reactive protein (CRP) interacts with phosphorylcholine (PC), Fcgamma 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.
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| 8. |
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| 9. |
- Skogh, Thomas, et al.
(författare)
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The B cells are back!
- 2005
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Ingår i: Drug Discovery Today. - : Elsevier BV. - 1740-6765. ; 2:3, s. 351-357
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Forskningsöversikt (refereegranskat)abstract
- New interest has emerged regarding the central roles of B cells in physiological immunoregulation and immunopathogenesis of rheumatoid arthritis (RA), a condition traditionally viewed as T-cell mediated. Thus, B cells, autoantibodies, immune complexes, complement and their cellular receptors are experiencing renewed interest concerning their roles in the initiation and propagation of arthritis. The discovery of citrullinated proteins as targets of autoimmune response in RA has implications regarding aetiopathogenesis, prediction of future disease, diagnosis of recent onset and established arthritis and prediction of disease course and disease outcome. Antibody-based therapies against cytokines, cytokine receptors and B cells contribute to the important advances in antirheumatic therapy. © 2005 Elsevier Ltd. All rights reserved.
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| 10. |
- Skoglund, Caroline, 1981-, et al.
(författare)
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C-reactive protein inhibit complement-mediated platelet activation suggesting a protective role in atherogenesis
- 2006
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Ingår i: Atherosclerosis Supplements. - Clare, Ireland : Elsevier. - 1567-5688 .- 1878-5050. ; 7:3, s. 284-284
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Objective: C-reactive protein (CRP) represents a powerful predictor of coro- nary artery disease. However, its physiological role is not fully understood. The binding of CRP to its ligand phosphorylcholine (PC) activates the com- plement system via the classical pathway, although limited to the initial stages, i.e. no membrane attack complex is formed. The aim of this study was to chaxacterize CRP-induced complement activation on PC-coated surfaces, and to investigate the regulatory effects of PC-bound crp on complement induced platelet activation.Methods: PC conjugated to keyhole limpet hemocyanin was immobilized to cross-linked fibrinogen on silica particles. Ellipsometry and polyclonal anti- bodies were used to quantify deposition of serum proteins, complement factors and CRP on the surfaces. Washed platelets as well as serum were prepared according to standard protocols. CRP concentrations were measured with a high sensitivity assay. Lumi-aggregometry was used to evaluate the effects of PC-coated particles and CRP on complement-induced platelet aggregation and secretion.Results: Serum (5%) induced platelet aggregation and secretion through complement-dependent mechanisms. PC-coated particles antagonized the complement-mediated platelet activation but only if CRP was present. Inter- estingly, we found that a minor elevation of CRR below 5 rag/1 was sufficient to inhibit platelet activation.Conclusions: We suggest that CRP bound to PC-expressing ligands, e.g. bacteria or modified low-density lipoproteins in an atherosclerotic lesion, modulate complement activation and thereby prevent a harmful platelet activation.
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