Tissue-Type Plasminogen Activator Deficiency Exacerbates Arthritis

Yang, Yuan; Carmeliet, Peter; Hamilton, John A.

doi:10.4049/jimmunol.167.2.1047

Cited by 57 publications

(68 citation statements)

References 34 publications

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“…Staining for fibrin was often prominent along articular surfaces exhibiting cartilage degradation, but was also observed throughout inflamed joint tissues (Figure 2, J and K). As previously reported by other investigators (16,19), fibrin staining in joints from CII-immunized Fib + mice appeared to correlate with the degree of joint pathology and was less apparent in the joints of challenged mice lacking other…”

Section: Figuresupporting

confidence: 60%

“…Fibrin deposition is one of the most conspicuous and consistent features of both human RA and experimental animal models of arthritic disease, documented in areas of synovial hemorrhage and necrosis and more broadly in areas of synovial inflammation and hyperplasia and along articular surfaces (16,18,19). Furthermore, fibrin(ogen) is a key component of particulate "rice bodies" within synovial fluid (18).…”

Section: Introductionmentioning

confidence: 99%

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Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Flick

LaJeunesse²,

Talmage³

et al. 2007

J. Clin. Invest.

154

148

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Fibrin deposition within joints is a prominent feature of arthritis, but the precise contribution of fibrin(ogen) to inflammatory events that cause debilitating joint damage remains unknown. To determine the importance of fibrin(ogen) in arthritis, gene-targeted mice either deficient in fibrinogen (Fib -) or expressing mutant forms of fibrinogen, lacking the leukocyte receptor integrin α M β 2 binding motif (Fibγ 390-396A ) or the α IIb β 3 platelet integrin-binding motif (Fibγ Δ5 ), were challenged with collagen-induced arthritis (CIA). Fib -mice exhibited fewer affected joints and reduced disease severity relative to controls. Similarly, diminished arthritis was observed in Fibγ 390-396A mice, which retain full clotting function. In contrast, arthritis in Fibγ Δ5 mice was indistinguishable from that of controls. Fibrin(ogen) was not essential for leukocyte trafficking to joints, but appeared to be involved in leukocyte activation events. Fib -and Fibγ 390-396A mice with CIA displayed reduced local expression of TNF-α, IL-1β, and IL-6, which suggests that α M β 2 -mediated leukocyte engagement of fibrin is mechanistically upstream of the production of proinflammatory mediators. Supporting this hypothesis, arthritic disease driven by exuberant TNF-α expression was not impeded by fibrinogen deficiency. Thus, fibrin(ogen) is an important, but context-dependent, determinant of arthritis, and one mechanism linking fibrin(ogen) to joint disease is coupled to α M β 2 -mediated inflammatory processes.

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Section: Figuresupporting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Flick

LaJeunesse²,

Talmage³

et al. 2007

J. Clin. Invest.

154

148

View full text Add to dashboard Cite

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“…Deimination of fibrin could hamper its cleavage by plasmin, arginyl residues being included in the cleavage sites of this enzyme. The subsequent defect in fibrinolysis could have a role in perpetuating inflammation because fibrin accumulation in the ST has been demonstrated to play a pathogenic role in various animal models of arthritis (52)(53)(54). As, in this work, we demonstrate the presence of deiminated fibrin in other rheumatic diseases associated with synovitis, a deiminationrelated defect in fibrinolysis could constitute a general phenomenon contributing to the maintenance of ST inflammation.…”

Section: Discussionmentioning

confidence: 75%

Fibrin Deimination in Synovial Tissue Is Not Specific for Rheumatoid Arthritis but Commonly Occurs during Synovitides

Chapuy‐Regaud

Sebbag

Baeten

et al. 2005

The Journal of Immunology

118

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Autoantibodies to deiminated (citrullinated) proteins are the most specific serological markers of rheumatoid arthritis (RA). Deimination is critical in generating the peptidic epitopes they recognize. In the synovial tissue (ST), deiminated forms of the α- and β-chains of fibrin are their major autoantigenic targets (anti-human fibrin(ogen) autoantibodies (AhFibA)). We investigated whether the presence of deiminated fibrin in the ST was specific for RA, because this could explain why AhFibA are RA specific. In 13 patients with RA and 19 patients with various other rheumatological disorders, knee ST biopsies were collected in macroscopically inflamed areas identified under arthroscopy. Synovitis was histopathologically confirmed in all of the biopsies. By immunoblotting, using antisera to fibrin, Abs to citrullyl residues, and AhFibA purified from RA sera, deiminated fibrin was evidenced in ST extracts from all of the patients. Moreover, variations in the degree of fibrin deimination were observed that were not related to the disease. Immunohistochemical analysis, using Abs to citrullyl residues and an antiserum to fibrin on adjacent serial sections of ST, confirmed the results because deiminated proteins colocalized with fibrin in RA as well as in control patients. Therefore, fibrin deimination in the ST is a general phenomenon associated to any synovitis, which does not necessarily induce a B autoimmune response with production of AhFibA.

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“…T hrombosis is a characteristic but incompletely understood element of inflammation, innate immune responses, and acquired immune disorders (1)(2)(3)(4)(5). Localized induction of procoagulant molecules on the vascular endothelium is thought to play an important role in this process.…”

mentioning

confidence: 99%

Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

Ghanekar

Mendicino

Líu

et al. 2004

The Journal of Immunology

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Thrombosis is a prominent feature of acute vascular rejection (AVR), the current barrier to survival of pig-to-primate xenografts. Fibrinogen-like protein 2 (fgl2/fibroleukin) is an inducible prothrombinase that plays an important role in the pathogenesis of fibrin deposition during viral hepatitis and cytokine-induced fetal loss. We hypothesized that induction of fgl2 on the vascular endothelium of xenografts contributes to thrombosis associated with AVR. We first examined fgl2 as a source of procoagulant activity in the pig-to-primate combination. The porcine fgl2 (pfgl2) was cloned and its chromosomal locus was identified. Recombinant pfgl2 protein expressed in vitro was detected on the cell surface and generated thrombin from human prothrombin. Studies of pig-to-baboon kidney xenografts undergoing AVR in vivo revealed induction of pfgl2 expression on graft vascular endothelial cells (ECs). Cultured porcine ECs activated by human TNF-α in vitro demonstrated induction of pfgl2 expression and enhanced activation of human prothrombin. The availability of gene-targeted fgl2-deficient mice allowed the contribution of fgl2 to the pathogenesis of AVR to be directly examined in vivo. Hearts heterotopically transplanted from fgl2+/+ and fgl2+/− mice into Lewis rats developed AVR with intravascular thrombosis associated with induction of fgl2 in graft vascular ECs. In contrast, xenografts from fgl2−/− mice were devoid of thrombosis. These observations collectively suggest that induction of fgl2 on the vascular endothelium plays a role in the pathogenesis of AVR-associated thrombosis. Manipulation of fgl2, in combination with other interventions, may yield novel strategies by which to overcome AVR and extend xenograft survival.

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Tissue-Type Plasminogen Activator Deficiency Exacerbates Arthritis

Cited by 57 publications

References 34 publications

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Fibrin(ogen) exacerbates inflammatory joint disease through a mechanism linked to the integrin αMβ2 binding motif

Fibrin Deimination in Synovial Tissue Is Not Specific for Rheumatoid Arthritis but Commonly Occurs during Synovitides

Endothelial Induction of fgl2 Contributes to Thrombosis during Acute Vascular Xenograft Rejection

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