Essential Role for the C5a Receptor in Regulating the Effector Phase of Synovial Infiltration and Joint Destruction in Experimental Arthritis

Grant, Ethan P.; Picarella, Dominic; Burwell, Timothy; Delaney, Tracy; Croci, Alisa; Avitahl, Nicole; Humbles, Alison A.; Gutierrez-Ramos, José-Carlos; Briskin, Michael; Gérard, Craig; Coyle, Anthony J.

doi:10.1084/jem.20020205

Cited by 142 publications

(120 citation statements)

References 39 publications

(43 reference statements)

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“…Recent studies in mice deficient in members of the complement system have 2546 LI ET AL shown that both alternative and classical pathways of complement activation are important in the development of arthritis in CIA as well as in CII antibodyinduced arthritis (36)(37)(38). Provided that plasmin plays an essential role in complement activation, these findings are consistent with our results in plasminogen-deficient mice in CIA.…”

Section: Discussionsupporting

confidence: 91%

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Guo

Holmdahl

et al. 2005

Arthritis & Rheumatism

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Objective. To investigate the contrasting roles of plasminogen deficiency between models of collageninduced arthritis (CIA) and antigen-induced arthritis (AIA).Methods. We developed a new animal model of arthritis, which we have called local injection-induced arthritis (LIA). In this model, we replaced methylated bovine serum albumin, which is normally used as an immunogen and is injected intraarticularly into the knee joint, with type II collagen (CII) to induce AIA. The severity of CIA, LIA, and AIA in wild-type and plasminogen-deficient mice was evaluated by clinical scoring or histologic grading. Necrosis was determined by histology and immunohistochemistry.Results. After CII immunization alone, wild-type mice developed arthritis in most of the paws as well as in the knee joints, whereas plasminogen-deficient mice were totally resistant to the disease. Local knee injections of CII or saline slightly enhanced the severity of the knee arthritis in wild-type mice during a 60-day experimental period. Unexpectedly, the plasminogendeficient mice also developed arthritis in joints that were injected with CII or saline. However, the arthritis was milder than that in their wild-type littermates. Sustained tissue necrosis was found only in the plasminogen-deficient mice after the local injection.Conclusion. Our data show that both the antigen and the joint trauma caused by the local injection are critical to explaining the contrasting roles of plasminogen deficiency in CIA and AIA. This further indicates that CIA and AIA have distinct pathogenic mechanisms. The data also suggest that plasmin may be required for the induction of these arthritis models that are critically dependent on complement activation.

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Section: Discussionsupporting

confidence: 91%

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Guo

Holmdahl

et al. 2005

Arthritis & Rheumatism

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“…Recently, it has been shown that the C5a receptor plays a critical role in the effector phase of synovial infiltration and joint destruction [27]. To assess the importance of the early components of complement activation for the antibody-mediated effector phase of arthritis, we used arthritogenic monoclonal antibodies to CII [8,14] to induce arthritis in C3 -/-, FB -/-, and control DBA/1J mice.…”

Section: Discussionmentioning

confidence: 99%

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis

et al. 2004

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To analyze the role of the classical and alternative pathways of complement activation in the effector phase of arthritis, we have induced arthritis in C3-and factor B (FB)-deficient (C3 -/-and FB -/-) DBA/1J mice using well-defined monoclonal IgG2b and IgG2a antibodies to type II collagen. In control DBA/1J mice, severe swelling of the joints, destruction of cartilage and erosion of bone developed very rapidly with a 100% incidence and a peak on days 7-10. Although 75% of C3 -/-mice developed arthritis, the clinical severity was very mild and the onset was delayed. Severity of arthritis in FB -/-mice ranked intermediate in comparison with C3 -/-and control mice with an incidence of 100%. Immunohistochemical analysis of the inflamed joints demonstrated substantial reduction in macrophage and neutrophilic leukocyte infiltration in both C3 -/-and FB -/-mice, thereby confirming the clinical findings. We conclude that both the classical and the alternative pathways of complement activation are involved in the effector phase of arthritis.

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“…VCAM-1 was reduced in DTHA paws following anti-C5aR treatment, and as C5aR is expressed on endothelial cells and synovial fibroblasts [7] this reduction in VCAM-1 could represent a direct effect of anti-C5aR treatment on these cells. In support of this, it has been shown that C5aR À/À mice have lower expression of VCAM-1 mRNA than wild-type mice after induction of CAIA [19].…”

Section: Discussionmentioning

confidence: 62%

“…Complement activation and C5a production in DTHA most likely takes place at the cartilage surfaces where the anti-CII administered during induction localises and forms immune complexes with cartilage CII. In the CAIA and CIA models anti-CII antibodies deposit on cartilage surfaces and activate complement [19,33], and in the K/BxN and K/BxN serum transfer models glucose-6-phosphate isomerase (GPI)-anti-GPI immune complexes deposit on the cartilage surfaces and activate complement [34]. Cartilage surfaces are not very rich in cells and thus lack the cell membrane-bound C3 inactivators decay-acceleration factor (DAF) and membrane cofactor protein (MCP), so only soluble inhibitors and surface sialic acid residues are present to dampen the activation of complement pathways [34].…”

Section: Discussionmentioning

confidence: 99%

“…A vaccine that induces generation of anti-C5a antibodies has been shown to be effective in murine collagen-induced arthritis (CIA) in mice [16], and oral treatment with a small molecule C5a antagonist reduced joint damage in the rat antigen-induced arthritis model [17]. In several mouse models of arthritis C5aR-deficient mice show reduced disease development [18][19][20][21]. In human C5aR knockin mice, a mouse anti-human C5aR monoclonal antibody effectively ameliorated neutrophil-dependent K/B Â N serum transfer-induced arthritis [22], and it has been shown that antimouse C5aR mAb lowers disease activity when administered in the early stages of murine CIA [23].…”

Section: Introductionmentioning

confidence: 99%

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Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

et al. 2015

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(2015) Treatment with anti-C5aR mAb leads to earlyonset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model, Autoimmunity, 48:7, 460-470, DOI: 10.3109/08916934.2015 Department of Cell Biology, Novo Nordisk A/S, Beijing, China AbstractBlockade of the complement cascade at the C5a/C5a receptor (C5aR)-axis is believed to be an attractive treatment avenue in rheumatoid arthritis (RA). However, the effects of such interventions during the early phases of arthritis remain to be clarified. In this study we use the murine delayed-type hypersensitivity arthritis (DTHA) model to study the very early effects of a blocking, non-depleting anti-C5aR mAb on joint inflammation with treatment synchronised with disease onset, an approach not previously described. The DTHA model is a single-paw inflammatory arthritis model characterised by synchronised and rapid disease onset driven by Tcells, immune complexes and neutrophils. We show that a reduction in paw swelling, bone erosion, cartilage destruction, synovitis and new bone formation is apparent as little as 60 h after administration of a single dose of a blocking, non-depleting anti-mouse C5aR mAb. Importantly, infiltration of neutrophils into the joint and synovium is also reduced following a single dose, demonstrating that C5aR signalling during the early stage of arthritis regulates neutrophil infiltration and activation. Furthermore, the number of T-cells in circulation and in the draining popliteal lymph node is also reduced following a single dose of anti-C5aR, suggesting that modulation of the C5a/C5aR axis results in effects on the T cell compartment in inflammatory arthritis. In summary, these data demonstrate that blockade of C5aR leads to rapid and significant effects on arthritic disease development in a DTHA model strengthening the rationale of C5aR-blockade as a treatment strategy for RA, especially during the early stages of arthritis flare.

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Essential Role for the C5a Receptor in Regulating the Effector Phase of Synovial Infiltration and Joint Destruction in Experimental Arthritis

Cited by 142 publications

References 39 publications

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

Complement activation by both classical and alternative pathways is critical for the effector phase of arthritis

Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

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