Evaluation of classical complement pathway activation in rheumatoid arthritis: Measurement of C1q–C4 complexes as novel activation products

Wouters, Diana; Voskuyl, Alexandre E.; Molenaar, Esmeralda T. H.; Dijkmans, Ben A. C.; Hack, C. Erik

doi:10.1002/art.21729

Cited by 51 publications

(42 citation statements)

References 32 publications

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“…The complement system has been shown to play a role in both initiating the inflammatory state as well as in maintaining the inflammation during chronic disease. Complement activation products, such as C3d (34), C1q-C4 complexes (35), sC5b-9, and the fragment Bb (36), can be found in the synovial fluid of patients with active arthritis, indicating ongoing activation of complement. Mice deficient in C3, factor B, and C5 are resistant to collagen-induced arthritis, an experimental model of rheumatoid arthritis, showing the importance of complement in the effector phase of chronic arthritis (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Complement Inhibitor C4b-Binding Protein Interacts Directly with Small Glycoproteins of the Extracellular Matrix

Happonen

Sjöberg

Mörgelin

et al. 2009

The Journal of Immunology

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Components derived from cartilage have been suggested to maintain the inflammation in joints in arthritis. Small leucine-rich repeat proteins (SLRPs) are structural components of cartilage important in organizing the meshwork of extracellular matrix components. It has recently been shown that the SLRP fibromodulin interacts with complement initiator C1q, leading to complement activation. The complement response is limited since fibromodulin also interacts with the complement inhibitor factor H. We have now found that osteoadherin, chondroadherin, fibromodulin, and proline arginine-rich end leucine-rich repeat protein bind to the complement inhibitor C4b-binding protein (C4BP). Using direct binding assays with C4BP fragments and C4BP mutants lacking individual domains in combination with electron microscopy, we have demonstrated that mainly the central core of C4BP mediated binding to SLRPs. Binding of SLRPs to C4BP did not affect its ability to inhibit complement. Osteoadherin, fibromodulin, and chondroadherin, which bind C1q and activate complement, were found to cause significantly higher C9 deposition in C4BP-depleted serum compared with Igs, indicating that the level of complement activation initiated by SLRPs is regulated by simultaneous binding to C4BP. A similar dual binding of C1q and complement inhibitors was observed previously for other endogenous ligands (amyloid, prions, C-reactive protein, and apoptotic cells) but not for exogenous activators (bacteria-bound Igs). These interactions can be significant during inflammatory joint diseases, such as rheumatoid arthritis, where cartilage is degraded, and cartilage components are released into synovial fluid, where they can interact with factors of the complement system.

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Section: Discussionmentioning

confidence: 99%

Complement Inhibitor C4b-Binding Protein Interacts Directly with Small Glycoproteins of the Extracellular Matrix

Happonen

Sjöberg

Mörgelin

et al. 2009

The Journal of Immunology

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“…C1q is known to play an important role in immune complex diseases, such as systemic lupus erythematosus, Arthus reaction, autoantibody-induced arthritis, glomerulonephritis, and experimental autoimmune encephalitis. 11,[64][65][66] In addition, mast cells have been associated with these diseases. 36,[67][68][69][70] Our findings provide a molecular mechanism linking C1q and activation of these inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between the α2β1 integrin and c-met/HGF-R regulates innate immunity

McCall-Culbreath¹,

Li²,

Zutter

2008

Blood

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Data from several investigators suggest that the ␣2␤1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1, endorepellin, and several viruses, is required for innate immunity and regulation of autoimmune/ allergic disorders. We demonstrated that the innate immune response to Listeria monocytogenes required ␣2␤1 integrin expression by peritoneal mast cells (PMCs). Ligation of the ␣2␤1 integrin by C1q contained in immune complexes comprised of Listeria and antibody was required for PMC activation in vitro and in vivo. However, ligation of the ␣2␤1 integrin alone was insufficient to activate cytokine secretion, suggesting that one or more additional signals emanating from a coreceptor were required for PMC activation. Here, we demonstrate that C1q, but neither other complement proteins nor FcR␥, is required for early innate immune response to Listeria. IntroductionThe role of the ␣2␤1 integrin in the innate and acquired immune response has been an area of active investigation. We initially reported that the ␣2␤1 integrin-deficient mice exhibited markedly diminished inflammatory responses to Listeria monocytogenes because of a requirement for ␣2␤1 integrin expression on peritoneal mast cells (PMCs) for mast-cell activation and cytokine release in vivo. 1 Although the ␣2␤1 integrin serves as a receptor for several matrix and nonmatrix ligands, the ligand for the integrin during the PMC response to infection was unknown. 2,3 We demonstrated that C1q complement protein and collectin family members, including mannose binding lectin and surfactant protein A, all served as ligands for the integrin. 4 In addition, the ␣2␤1 integrin was required for mast-cell activation in vitro in response to Listeria. However, ligation of the ␣2␤1 integrin alone was insufficient to activate cytokine secretion because mast-cell adhesion to collagen or C1q alone failed to support cytokine secretion. 4 We hypothesized that one or more additional signals emanating from an additional receptor was required to activate mast-cell cytokine secretion in response to immune complexes. At that time, we presented 2 alternative models by which ␣2␤1 integrin-ligand interactions may stimulate mast-cell activation and cytokine secretion. Our first model proposed that ligation of the ␣2␤1 integrin simultaneously with a second, costimulatory receptor elicited mast-cell activation, in a manner reminiscent of the role proposed for the ␣2␤1 integrin and the glycoprotein VI/Fc receptor common ␥ chain (FcR␥) during platelet adhesion to collagen. 5,6 In our second model, binding of the ␣2␤1 integrin to an immune complex containing C1q may directly activate the complement cascade, resulting in the deposition of C3b or iC3b and generation of complement byproducts, such as C3a or C5a, which would subsequently stimulate mast cell activation. [7][8][9] We now report that neither the FcR␥ nor components of the complement cascade are required in ␣2␤1 integrin-dependent mast-cell activation. Instead, we describe a novel coreceptor...

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“…Complement factors and receptors have been called to play an important role in RA since the first report from Brodeur in 1991 (14), and it is evident that synthesis and activation of complement take place at distinct sites within rheumatoid synovium (15). Reduced levels of native complement components and increased levels of complement metabolites in the synovial fluid and synovial tissue of RA patients have implicated complement in the pathogenesis of RA (16). It has been suggested that key components in complement activation, such as C3 and B, are produced locally in RA synovium rather than being plasma derived (17).…”

Section: Complement and Autoantibodiesmentioning

confidence: 99%

Complement System and Rheumatoid Arthritis: Relationships with Autoantibodies, Serological, Clinical Features, and Anti-TNF Treatment

Muzio

Perricone

Ballanti

et al. 2011

Int J Immunopathol Pharmacol

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The first two authors contributed equally to this work Autoantibodies (rheumatoid factor, RF; anti-citrullinated-protein antibodies,ACPA) and complement system are involved in rheumatoid arthritis (RA). ACPA and anti-TNF agents are capable of in vitro modulating complement activity. We investigated the relationships between complement, autoantibodies, and anti-TNF treatment in vivo. One-hundred fourteen RA patients (89F/25M), diagnosed according to 1987 ACR criteria, and 30 healthy controls were enrolled. Serological analysis included ESR, CRP, complement C3, C4 and CH50, RF and ACPA (ELISA, cut-off>20U/ml). Split-products (SP) of C3 and B were studied by immunoelectrophoresis/counterimmunoelectrophoresis. Seventy-six patients started anti-TNF treatment and were studied at baseline and after 22 weeks. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. At baseline, RA patients showed significantly higher levels of C3 and C4 than controls (C3 127.9±26.5 vs 1l0±25mgldl, P=O.0012; C4 29.7±10.2 vs 22.7±8.3mgldl, P=0.0003). No differences in C3, C4 and CH50 levels were observed between ACPA+ (n=76) and ACPA-(n=38) patients. After 22 weeks of anti-TNF, C3, C4 and RF were significantly reduced (P<0.003, <0.005 and <0.04, respectively) and RF changes showed negative correlation with CH50. SP of C3 and B were observed neither at baseline nor after 22 weeks. DAS28 significantly improved after 22 weeks. Patients showing higher baseline C3 or lower reduction of C3 levels after 22 weeks had a worse EULAR outcome (x2=22.793, P

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Evaluation of classical complement pathway activation in rheumatoid arthritis: Measurement of C1q–C4 complexes as novel activation products

Cited by 51 publications

References 32 publications

Complement Inhibitor C4b-Binding Protein Interacts Directly with Small Glycoproteins of the Extracellular Matrix

Complement Inhibitor C4b-Binding Protein Interacts Directly with Small Glycoproteins of the Extracellular Matrix

Crosstalk between the α2β1 integrin and c-met/HGF-R regulates innate immunity

Complement System and Rheumatoid Arthritis: Relationships with Autoantibodies, Serological, Clinical Features, and Anti-TNF Treatment

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