Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis–specific autoantibodies to citrullinated proteins complexed with fibrinogen

Clavel, C; Nogueira, Léonor; Laurent, Lætitia; Iobagiu, Cristina; Vincent, Christian; Sebbag, Mireille; Serre, Guy

doi:10.1002/art.23284

Cited by 249 publications

(232 citation statements)

References 45 publications

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“…The roles of synovium-based citrullinated fibrinogen and fibrin in the pathogenesis of RA disease are controversial; however, there is the possibility that both are associated with the onset and/or pathophysiology of RA. Citrullinated fibrinogen is reported to be an immunogenic molecule for ACPAs production [21][22][23], and citrullinated fibrin is a target of ACPAs [2] (but citrullinated fibrin is not specific to RA [24]) and antigen-antibody conflict induces and activates the proinflammatory effects in RA [24]. Finally, our results show that citrullinated fibrinogen is defective in FPA and FPB release and fibrin polymerization catalyzed by thrombin; however, we can not explain the pathological function of this phenomenon.…”

Section: Sds-page Conditions But Citrullinated Fibrinogen Did Not Unmentioning

confidence: 58%

Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization catalyzed by thrombin

Okumura¹,

Haneishi²,

Terasawa³

2009

Clinica Chimica Acta

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Section: Sds-page Conditions But Citrullinated Fibrinogen Did Not Unmentioning

confidence: 58%

Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization catalyzed by thrombin

Okumura¹,

Haneishi²,

Terasawa³

2009

Clinica Chimica Acta

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“…This finding has made considerable impact, as it has opened up the way to relevant and novel insights into RA-diagnosis and etiopathology (1). For example, ACPA are now part of the new American College of Rheumatology/ European League Against Rheumatism criteria for RA (18), and have been implicated in RA-pathogenesis, both in animal models (19)(20)(21) and in ex vivo human studies (22)(23)(24)(25). Importantly, the description of ACPA has led to the realization that RA constitutes at least two clinical syndromes that share many clinical features, but differ with respect to genetic background, predisposing environmental factors and clinical progression/remission (3,4,(26)(27)(28).…”

Section: Resultsmentioning

confidence: 99%

Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage

Shi

Knevel

Suwannalai

et al. 2011

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

477

577

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Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

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“…It may, for instance, be necessary to induce a marked reduction in ACPA levels to achieve clinical benefit when interfering with the humoral response, because ACPA-containing immune complexes could induce TNF production by macrophages (42).…”

Section: Discussionmentioning

confidence: 99%

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

Genovese¹,

Kinnman²,

Bourdonnaye³

et al. 2011

Arthritis & Rheumatism

116

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Objective. To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.Methods. The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level. Results.No statistically significant differences were observed in the efficacy end points at week 26 (P ‫؍‬ 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.Conclusion. This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

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Induction of macrophage secretion of tumor necrosis factor α through Fcγ receptor IIa engagement by rheumatoid arthritis–specific autoantibodies to citrullinated proteins complexed with fibrinogen

Cited by 249 publications

References 45 publications

Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization catalyzed by thrombin

Citrullinated fibrinogen shows defects in FPA and FPB release and fibrin polymerization catalyzed by thrombin

Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II, randomized, placebo-controlled, dose-finding trial

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