The effects of functional suppression of a membrane‐bound complement regulatory protein, CD59, in the synovial tissue in rats

Mizuno, Masashi; Nishikawa, Kazuhiro; Goodfellow, Rhian; Piddlesden, Sara J.; Morgan, B. Paul; Matsuo, Seiichi

doi:10.1002/art.1780400319

Cited by 33 publications

(41 citation statements)

References 20 publications

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“…The findings fully support our reported description of an acute complement-dependent arthritis induced by blocking CD59 in situ in the rat knee joint (15,16). It is important to note that CD59a Ϫ/Ϫ mice did not spontaneously develop arthritis as might have been anticipated from the blocking experiments in rats.…”

Section: Discussionsupporting

confidence: 90%

“…These findings suggested to us that CD59 might be key to the protection of the synovial membrane, and that loss of CD59 expression in RA might render the rheumatoid synovium susceptible to damage by the MAC. To investigate this possibility, we injected rat knee joints with a monoclonal antibody (mAb) that specifically blocked the activity of CD59 and showed that this provoked a spontaneous, acute, complement-dependent arthritis (15,16). Blockade of CD59 (together with the rodentspecific complement regulator Crry) also exacerbated disease in the CIA model in rats (17).…”

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confidence: 99%

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Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Williams¹,

Mizuno²,

Richards³

et al. 2004

Arthritis & Rheumatism

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Objective. To investigate the roles of CD59a in the protection of joint tissue in the context of murine antigen-induced arthritis (AIA).Methods. AIA was triggered in CD59a-deficient (CD59a ؊/؊ ) mice and in CD59a-sufficient (CD59a ؉/؉ ) controls; the course and severity of disease were compared between groups. The effects on arthritis of restoring CD59 to the joint in CD59a ؊/؊ mice by use of a membrane-targeted recombinant CD59 were also explored.Results. Disease, as assessed clinically by measurement of joint swelling on day 1 (P < 0.0001), day 2 (P < 0.01), and day 7 (P < 0.02) and histologically from indicators of joint damage on day 21 (P < 0.02), was significantly enhanced in CD59a ؊/؊ mice compared with CD59a؉/؉ wild-type controls. Membrane attack complex (MAC) deposition in the arthritic joints of CD59a ؊/؊ mice was also increased compared with that in the joints of CD59a ؉/؉ controls. Restitution of CD59 activity in joints of CD59a ؊/؊ mice was attempted with soluble recombinant rat CD59 (sCD59) or with a novel membrane-targeted rat CD59 derivative (sCD59-APT542). Strong immunohistochemical staining of the synovial membrane and subsynovial tissue was apparent in sCD59-APT542-injected joints, but not in joints injected with untargeted sCD59. Intraarticular administration of sCD59-APT542 markedly ameliorated disease severity in CD59a ؊/؊ mice, knee swelling was significantly reduced over the time course of the disease, and joint damage, assessed histologically, was significantly milder on day 21 (P < 0.05).Conclusion. These data firmly implicate the MAC of complement as a major effector of joint damage in the murine AIA model of rheumatoid arthritis (RA), and they provide a rationale for the inhibition of MAC assembly as a therapeutic strategy for RA.

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Williams¹,

Mizuno²,

Richards³

et al. 2004

Arthritis & Rheumatism

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“…Endogenous expression of complement regulatory proteins appears to be important in resistance to inflammatory disease as blockade of both Crry and CD59 led to more severe CIA in rats (18). The results of earlier studies indicated that endogenous expression of CD59 may play a role in protection against synovial injury mediated by the membrane attack complex as inhibition of CD59 led to an acute, transient arthritis (36). The importance of local complement regulatory proteins is further supported by the beneficial effect of an intra-articular injection of a truncated form of human CR1 in Ag-induced arthritis in rats (37).…”

Section: Discussionmentioning

confidence: 99%

Prevention of Collagen-Induced Arthritis in Mice Transgenic for the Complement Inhibitor Complement Receptor 1-Related Gene/Protein y

Banda

Kraus

Muggli

et al. 2003

The Journal of Immunology

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The objective of these studies was to examine collagen-induced arthritis (CIA) in C57BL/6 mice transgenic for the rodent complement regulatory protein complement receptor 1-related gene/protein y (Crry) (Crry-Tg), a C3 convertase inhibitor. The scores for clinical disease activity and for histological damage in the joints were both significantly decreased in Crry-Tg mice in comparison to wild-type (WT) littermates. The production of both IgG1 and IgG2a anti-collagen Abs was reduced in the Crry-Tg mice, although spleen cell proliferation in response to collagen type II was not altered. The production of IFN-γ, TNF-α, and IL-1β by LPS-stimulated spleen cells was decreased, and IL-10 was increased, in cells from Crry-Tg mice in comparison to WT. The steady-state mRNA levels for IFN-γ, TNF-α, and IL-1β were all decreased in the joints of Crry-Tg mice in comparison to WT. The synovium from Crry-Tg mice without CIA contained the mRNA for the Crry transgene, by RT-PCR, and the synovium from transgenic mice with CIA exhibited little deposition of C3 protein by immunohistological analysis. These results suggest that suppression of CIA in Crry-Tg mice may be due to enhanced synthesis of Crry locally in the joint with decreased production of proinflammatory cytokines.

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“…The bound mAbs were detected using FITClabeled rabbit anti-mouse IgG (Cappel Labs) absorbed with normal rat serum. To observe C3b and membrane attack complex (MAC; C5b-9) deposition, we used FITC-rabbit anti-rat C3 (Cappel Labs) and polyclonal (pc) rabbit anti-rat C9, respectively (22,25,26), followed by incubation with FITC-goat anti-rabbit IgG (Cappel Labs). We also used the anti-human C3b mAb C3/30 that cross-reacts with rat C3b (27).…”

Section: Chemicals and Absmentioning

confidence: 99%

“…This schedule of CVF administration was planned from our previous data showing that systemic complement was depleted for at least 72 h following a single 25-U CVF injection (31). Systemic complement suppression was confirmed by measuring serum complement hemolytic activities as described previously (25). As the control, the same amount of sterile isotonic saline was injected in another group of rats subjected to the group 2 protocol (group7, n ϭ 6; Table I).…”

Section: Systemic Complement Depletion In Zymosan-induced Peritonitismentioning

confidence: 99%

Zymosan, but Not Lipopolysaccharide, Triggers Severe and Progressive Peritoneal Injury Accompanied by Complement Activation in a Rat Peritonitis Model

Mizuno

Ito

Hepburn

et al. 2009

The Journal of Immunology

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Fungal peritonitis is an important complication in peritoneal dialysis patients; either continuous or recurrent peritonitis may enhance peritoneal damage. Even when the peritoneal dialysis catheter is removed in patients with fungal peritonitis, peritoneal fibrosis can progress and evolve into encapsular peritoneal sclerosis. It is unclear why fungal infections are worse than bacterial in these respects. Zymosan is a cell wall component of yeast that strongly activates the complement system. In this study, we compared the effects of zymosan and bacterial LPS on peritoneal inflammation in a rat peritoneal injury model induced by mechanical scraping. Intraperitoneal administration of zymosan, but not LPS or vehicle, caused markedly enhanced peritonitis with massive infiltration of cells and deposition of complement activation products C3b and membrane attack complex on day 5. In rats administered zymosan and sacrificed on days 18 or 36, peritoneal inflammation persisted with accumulation of ED-1-positive cells, small deposits of C3b and membrane attack complex, exudation of fibrinogen, and capillary proliferation in subperitoneal tissues. When zymosan was administered daily for 5 days after peritoneal scrape, there was even greater peritoneal inflammation with peritoneal thickening, inflammatory cell accumulation, and complement deposition. Inhibition of systemic complement by pretreatment with cobra venom factor or local inhibition by i.p. administration of the recombinant complement regulator Crry-Ig reduced peritoneal inflammation in zymosan-treated rats. Our results show that yeast components augment inflammation in the injured peritoneum by causing complement activation within the peritoneal cavity. Local anticomplement therapy may therefore protect from peritoneal damage during fungal infection of the peritoneum.

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The effects of functional suppression of a membrane‐bound complement regulatory protein, CD59, in the synovial tissue in rats

Cited by 33 publications

References 20 publications

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Deletion of the gene encoding CD59a in mice increases disease severity in a murine model of rheumatoid arthritis

Prevention of Collagen-Induced Arthritis in Mice Transgenic for the Complement Inhibitor Complement Receptor 1-Related Gene/Protein y

Zymosan, but Not Lipopolysaccharide, Triggers Severe and Progressive Peritoneal Injury Accompanied by Complement Activation in a Rat Peritonitis Model

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