A fibrin based model for rheumatoid synovitis

Sánchez‐Pernaute, Olga; Largo, Raquel; Calvo, Emílio; Alvarez-Soria, M A; Egido, Jesús; Herrero‐Beaumont, Gabriel

doi:10.1136/ard.2003.011767

Cited by 46 publications

(43 citation statements)

References 36 publications

(26 reference statements)

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“…In human AAA, although an association between fibrinogen, fibrin degradation products (i.e., D-dimer), and aneurysm size/progression has long been recognized (27,28), a causal relationship has not been clearly established. The massive deposition of fibrin/fibrinogen and/or fibrin degradation products in human AAA tissue (26) is reminiscent of the increased local accumulation of fibrin/fibrinogen in the inflamed joints of individuals with rheumatoid arthritis (RA) (29), a disease in which autoantibody response to fibrinogen, specifically citrulline-modified fibrinogen (a process whereby the arginine residues of fibrinogen are converted to citrulline), is not only diagnostic but is thought to contribute to disease pathogenesis (30). Whether circulating antibodies with fibrinogen specificity drive the pathogenesis of human AAA and/or serve as biomarkers for disease progression in this subset of AAA patients remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastaseperfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase-induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA.A bdominal aortic aneurysm (AAA) is a common vascular disorder that affects ∼5% of men and ∼1.5% of women ages 65 and older (1, 2). Rupture of AAA presents a medical emergency that accounts for 15,000 deaths annually in the United States (3). Currently, surgical repair represents the only treatment option for large AAAs, whereas surgery in small AAAs offers no clear overall long-term survival advantage (4, 5). Thus, medical management, to inhibit or reverse the progression of small AAAs, has received increasing attention. Major challenges remain in the development of therapeutic agents that impede aneurysm expansion, as our understanding of the pathophysiology underlying this disease is incomplete.One of the defining characteristics of AAA is inflammation accompanied by a cellular infiltrate that is predominantly lymphocytic (6-8). The elastase-induced AAA mouse model recapitulates many key features of human AAA, including the inflammatory response (9). We previously established with this model that aneurysm development requires factor B and properdin of the complement alternative pathway (AP) (10, 11). We showed that mice deficient in B cells (and hence antibodies), called μMT mice, are protected against aneurysm formation. Reconstitution with natural IgG, but not IgM, from wild-type mice res...

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Section: Discussionmentioning

confidence: 99%

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Zhou

Yan

Bertram

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, HMGB1, in contrast to heat shock proteins, was already described to stimulate the TLR pathways in RA (van Beijnum et al, 2008). (Gormsen et al, 1971;Sanchez-Pernaute et al, 2003), fibrin could contribute to the stimulation of RASF via the induction of the TLR4 pathway.…”

Section: Toll-like Receptors (Tlr) In Ramentioning

confidence: 99%

Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis

Rodrigues

Jüngel

2009

Molecular Immunology

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Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the progressive and irreversible destruction of joints.RA remains an incurable condition, although a new class of drugs, biologicals, have made a major breakthrough in targeting and/or eliminating the immune cells, including T cells, B cells and monocytes/macrophages from the joints. That we cannot (yet?) cure the disease is most likely due to the lack of therapeutic targeting the endogenously activated RA synovial fibroblasts (RASF).Most interestingly, RASF express Toll-like receptors 1-6 rendering them prone to activation by exogenous and endogenous TLR ligands and resulting in the production of numerous powerful chemokines and cytokines. These factors are responsible for the repopulation of immune cells in the joints after ceasing cell depleting therapies.To characterize the molecular mechanisms of synovial activation, a new approach studying the epigenetic characteristics of RASF has been recently undertaken.Thereby, the pattern of histone acetylation, DNA methylation and gene expression regulating microRNA are being explored.Since auto-antibodies have the most predictive and diagnostic value for RA, it is challenging to study more comprehensively the contribution of auto-antibodies to the disease. A new screening technique, serological analysis of recombinant human cDNA expression library (SEREX), adapted from cancer research allowed for the identification of novel auto-antibodies in RA, including anti-serpin E2 auto-antibodies.The serpin E2 auto-antibodies were found to inhibit the activity of serpin E2 and have potentially a functional role in the disease. The recent findings in the field of innate immunity, epigenetics and autoimmunity related to the pathogenesis of RA are in the scope of this review. 2

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“…Furthermore, the increase in cathepsin K producing fibroblast-like cells at sites of synovial vascularisation and angiogenesis may indicate a role for this protease in the loosening of the matrix to facilitate angiogenic growth (Hou et al, 2001(Hou et al, , 2002. It has been proposed that pannus formation in rheumatoid arthritis is initiated by the formation of fibrin clots within the synovial fluid at the synovial surface, which provide a scaffold into which synovial fibroblast-like cells migrate (Sánchez-Pernaute et al, 2003). This model proposes that, as is observed in other inflammatory conditions (Berckmans et al, 2002), inflammation induces an influx of plasma components into the synovial fluid including components of the coagulation cascade which become activated; but that in rheumatoid arthritis there is an imbalance between coagulation and fibrinolysis leading to the formation and persistence of clots (Andersen & Gormsen, 1970).…”

Section: Synovium: Inflammation Hyperplasia Pannus Formation and Prmentioning

confidence: 99%

“…The coagulation cascade comprises a proteolytic activation series of serine protease ending in thrombin which then cleaves fibrinogen to fibrin (Cirino, Napoli, Bucci, & Cicala, 2000), whereas fibrinolysis is mediated by plasmin, which is generated by the activa- Table 3 Summary of proteases with pathological roles in synovium Saarinen et al (1994) tion of plasminogen by proteases such as urokinase-type plasminogen activator (uPA) and tissue plasminogan activator (Cesarman-Maus & Hajjar, 2005). The imbalance in these processes has been suggested to arise either due to the cleavage of uPA by thrombin which generates a proteolytically inactive form or through an increased expression of inhibitors of fibrinolysis (Braat, Jie, Ronday, Beekman, & Rijken, 2000;Ronday et al, 1996;Sánchez-Pernaute et al, 2003). It is also suggested that the persistence of fibrin in synovial fluids results in MMP-mediated cleavage of fibrin, which may generate unusual fibrin epitopes that contribute to autoimmunity (Bini, Wu, Schnuer, & Kudryk, 1999;Sánchez-Pernaute et al, 2003).…”

Section: Synovium: Inflammation Hyperplasia Pannus Formation and Prmentioning

confidence: 99%

“…The imbalance in these processes has been suggested to arise either due to the cleavage of uPA by thrombin which generates a proteolytically inactive form or through an increased expression of inhibitors of fibrinolysis (Braat, Jie, Ronday, Beekman, & Rijken, 2000;Ronday et al, 1996;Sánchez-Pernaute et al, 2003). It is also suggested that the persistence of fibrin in synovial fluids results in MMP-mediated cleavage of fibrin, which may generate unusual fibrin epitopes that contribute to autoimmunity (Bini, Wu, Schnuer, & Kudryk, 1999;Sánchez-Pernaute et al, 2003). The role of protease-activated receptors (PARs) such as the thrombin-activated receptors PAR-1 and -3, and the plasmin receptor PAR-2, in synovium also merits further investigation (Ferrell et al, 2003;Shin et al, 1999) (Table 3).…”

Section: Synovium: Inflammation Hyperplasia Pannus Formation and Prmentioning

confidence: 99%

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The role of proteases in pathologies of the synovial joint

Jones¹,

Riley²,

Buttle³

2008

The International Journal of Biochemistry & Cell Biology

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Synovial (diarthrodial) joints are employed within the body to provide skeletal mobility and have a characteristic structure adapted to provide a smooth almost frictionless surface for articulation. Pathologies of the synovial joint are an important cause of patient morbidity and can affect each of the constituent tissues. A common feature of these pathologies is degenerative changes in the structure of the tissue which is mediated, at least in part, by proteolytic activity. Most tissues of the synovial joint are composed primarily of extracellular matrix and key pathological roles in the degeneration of this matrix are performed by metalloproteinases such as matrix metallproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). However, other proteases such as cathepsin K are likely to play an important role, especially in bone turnover. In addition to the cleavage of structural proteins, proteolytic activities are employed to regulate the activity of other proteases, growth factors, cytokines and other inflammatory mediators. Proteases combine to form complex regulatory networks, the correct functioning of which is required for tissue homeostasis and the imbalance of which may be a feature of pathology. A precise understanding of the proteases involved in these networks is required for a true understanding of the associated pathology.

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A fibrin based model for rheumatoid synovitis

Cited by 46 publications

References 36 publications

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Fibrinogen-specific antibody induces abdominal aortic aneurysm in mice through complement lectin pathway activation

Innate immunity, epigenetics and autoimmunity in rheumatoid arthritis

The role of proteases in pathologies of the synovial joint

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