IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA

Engelmann, Robby; Brandt, J.; Eggert, Martin; Karberg, Kirsten; Krause, Andreas; Neeck, Gunther; Mueller-Hilke, Brigitte

doi:10.1093/rheumatology/ken336

Cited by 62 publications

(53 citation statements)

References 15 publications

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“…In accordance with a recent study, 20 IgG1 followed by IgG4 were the predominant subclasses among anti-CCP antibodies ( Figure II in the online-only Data Supplement).…”

Section: Anti-ccps Antibodies Induce a Prooxidative Status In Healthysupporting

confidence: 92%

Anticyclic Citrullinated Protein Antibodies Are Implicated in the Development of Cardiovascular Disease in Rheumatoid Arthritis

Barbarroja

Pérez-Sánchez

Ruiz-Limón

et al. 2014

ATVB

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Objective— Previous studies have suggested a relationship between anticyclic citrullinated protein (CCP) levels and development of cardiovascular disease in rheumatoid arthritis (RA). However, a limited number of studies have demonstrated an involvement of anti-CCPs in those processes. This study was aimed to define the specific role of these auto-antibodies in the pro-oxidative, inflammatory, and proatherogenic profile observed in leukocytes from RA patients. Approach and Results— Seventy-five RA patients and 31 healthy donors were enrolled. Carotid intima media thickness was evaluated as atherosclerosis marker. Several procoagulant and inflammatory factors, leukocyte activation, and oxidative stress markers were analyzed in plasma and leukocyte subsets. Anti-CCPs were purified from plasma of RA patients, and in vitro treatment of healthy leukocytes was conducted. High titers of anti-CCPs were associated to altered expression of prothrombotic and inflammatory markers, high oxidative stress, and pathological carotid intima media thickness in RA patients. Notably, gene expression analysis showed that lymphocytes were major players in altered inflammatory profile, monocytes were responsible for the protrombotic and atherogenic status, and neutrophils mainly displayed a pro-oxidative feature. In vitro treatment with purified anti-CCPs fully recapitulated that pathogenic profile, promoting the activation of leukocytes. Conclusions— Anti-CCPs are key players in the inflammatory and proatherogenic status of RA patients. The effects are specific of the immune cell targeted, promoting overexpression of thrombotic, inflammatory, and pro-oxidative markers in monocytes; pro-oxidative status in neutrophils; and proinflammatory profile in lymphocytes. Targeting these autoantibodies would be an excellent strategy to prevent the development of cardiovascular disease in RA.

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“…In accordance with a recent study, 20 IgG1 followed by IgG4 were the predominant subclasses among anti-CCP antibodies ( Figure II in the online-only Data Supplement).…”

Section: Anti-ccps Antibodies Induce a Prooxidative Status In Healthysupporting

confidence: 92%

Anticyclic Citrullinated Protein Antibodies Are Implicated in the Development of Cardiovascular Disease in Rheumatoid Arthritis

Barbarroja

Pérez-Sánchez

Ruiz-Limón

et al. 2014

ATVB

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“…IgM, IgG3, and IgG1 are the most potent complement-activating isotypes, followed by IgG2 and IgA, whereas IgG4 and IgE do not activate complement. The anti-CCP antibody response involves all IgG subclasses as well as IgM and IgA (35,36). The traditional view that the antibodies IgM and multivalent IgG can activate the complement system only directly via the classical pathway has recently been challenged by observations that differentially glycosylated forms of IgG (37), IgM (33), and IgA (38,39) can also activate the alternative pathway and/or lectin pathway of complement (33,34,(37)(38)(39)(40).…”

Section: Discussionmentioning

confidence: 99%

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Trouw¹,

Haisma²,

Levarht³

et al. 2009

Arthritis & Rheumatism

218

149

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Objective. It has been suggested that anticitrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used.Methods. We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement.Results. Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place.Conclusion. Our findings indicate that anti-CCP antibodies activate the complement system in vitro via the classical and alternative pathways but not via the lectin pathway. These findings are relevant for the design of interventions aimed at inhibition of complement-mediated damage in RA.

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“…[3,4] The citrullination of arginine to citrulline possibly results in protein unfolding and consequent aberrant recognition by the immune system. These antibodies are thought to be triggered by the genes that increase susceptibility to RA as well as by many environmental agents.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Value of Autoantibodies Against Citrullinated Peptide Antigens in Rheumatoid Arthritis: Comparison of Different Commercial Kits

et al. 2011

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Amaç: Bu çalışmada romatoid faktörün (RF), anti-siklik sitrülin peptit (anti-CCP) antikorunun ve anti-mutat sitrülin vimentin (anti-MCV) antikorunun iki farklı ticari kitinin, ticari kitlerin performansları arasında önemli farklılıklar bulunabileceğini de göz önünde bulundurarak, romatoid artritteki (RA) tanısal değerleri test edildi. Bulgular:Otoantikorların tanısal duyarlılık ve özgüllüğünü belirlemek için yapılan alıcı işletim karakteristiği (ROC) eğrisi analizinde en yüksek eğri altında kalan alan değeri anti-CCP-2'ye aitti. Duyarlılık ve özgüllük RF için %88 ve %90, anti-CCP-2 için %84 ve %100, anti-MCV-548 için %80 ve %90 ve anti-MCV-248 için %84 ve %100 idi. DAS-28 ile anti-CCP-2 (r= 0.623), anti-MCV-548 (r= 0.481) ve anti-MCV-248 (r= 0.408) arasında zayıf bir korelasyon vardı. Ekstraartiküler tutulumu olan ve olmayan hastaların ve DAS-28'e göre düşük veya orta şiddette hastalık aktivitesi olan hastaların RF, anti-CCP-2, anti-MCV-548 ve anti-MCV-248 değerleri arasında istatistiksel olarak anlamlı bir fark yoktu.

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IgG1 and IgG4 are the predominant subclasses among auto-antibodies against two citrullinated antigens in RA

Cited by 62 publications

References 15 publications

Anticyclic Citrullinated Protein Antibodies Are Implicated in the Development of Cardiovascular Disease in Rheumatoid Arthritis

Anticyclic Citrullinated Protein Antibodies Are Implicated in the Development of Cardiovascular Disease in Rheumatoid Arthritis

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

Diagnostic Value of Autoantibodies Against Citrullinated Peptide Antigens in Rheumatoid Arthritis: Comparison of Different Commercial Kits

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