Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis

Kuhn, Kristine A.; Kulik, Liudmila; Tomooka, Beren; Braschler, Kristin J.; Arend, William P.; Robinson, William H.; Holers, V. Michael

doi:10.1172/jci25422

Cited by 479 publications

(412 citation statements)

References 52 publications

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“…The exact events leading to the formation of these antibodies are thus far unknown, as are the mechanisms by which they may contribute to tissue damage and inflammation. However, anti-CCP antibodies have been shown to aggravate collagen-induced arthritis in mice, which suggests that anti-CCP can be pathogenic (7,8).…”

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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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

View full text Add to dashboard Cite

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“…The presence of ACPAs in patients with recent-onset RA is predictive for progression to erosive RA (10,11), and their presence in patients with undifferentiated arthritis is highly predictive of progression to RA (12). Likewise, ACPAs were shown to contribute to disease progression in a mouse model of arthritis (13). Taken together, data from human and mouse studies indicate that ACPAs are a possible pathogenetic mechanism in RA.…”

mentioning

confidence: 89%

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Ioan‐Facsinay¹,

Willemze²,

Robinson³

et al. 2008

Arthritis & Rheumatism

166

144

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Objective. Anti-citrullinated protein antibodies (ACPAs) display high association with rheumatoid arthritis (RA) and are implicated in its pathogenesis. The presence of ACPAs is known to precede the onset of RA. In order to identify the features that could confer its pathogenicity, we extensively characterized this antibody response in a unique North American native population of patients with RA and their unaffected relatives.Methods. The levels of IgA, IgM, and IgG ACPAs, as well as IgM and IgA rheumatoid factor (RF), were measured in serum samples obtained from 81 patients with RA and 195 of their unaffected relatives. The isotype distribution, the fine specificity of the ACPA response, and its association with RF were compared in health and disease.Results. ACPA positivity was observed in 19% of the healthy relatives and ϳ91% of the patients with RA. ACPA isotype usage was strikingly lower in unaffected relatives than in patients with RA (1-2 versus 5-6 isotypes). Fine specificity studies showed that reactivity to citrullinated fibrinogen and vimentin was present in sera from patients with RA, while it was virtually absent in their unaffected relatives. Finally, the ACPA and RF responses were associated in patients with RA but were discordant in their healthy relatives. Extended analyses revealed that the presence of ACPAs was associated with RA irrespective of RF status, while the association of RF with disease relied on its interaction with ACPAs.Conclusion. The fine specificity and isotype usage of the ACPA response are qualitatively different in health and disease. Epitope spreading and expansion of the isotype repertoire might be necessary for development of RA, and this could be facilitated by the presence of RF antibodies.Autoantibodies are characteristic of a large number of autoimmune diseases. Determining the pathogenicity of autoantibodies by showing their capacity to transfer disease, however, is complicated by ethical and practical difficulties. Therefore, only a small minority of autoantibodies, such as antiplatelet antibodies in idiopathic thrombocytopenia purpura or the antidesmoglein antibodies in pemphigus vulgaris, were convincingly shown to mediate a pathogenetic effect through placental transfer (1) or transfer into experimental animals (2), respectively.

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“…In the past decade, considerable interest was devoted to autoantibodies against citrullinated proteins, proteins in which the amino acid arginine is posttranslationally modified to the nonstandard amino acid citrulline. In mice, it has been shown that infusion of ACPAs into animals with arthritis leads to exacerbation of arthritis, whereas a reduction in ACPA levels is associated with a less severe disease (9). These data indicate that ACPAs are directly involved in the progression of arthritis, but that they are not endowed with the capacity to induce arthritis in healthy hosts.…”

Section: Autoantibodiesmentioning

confidence: 99%

Emerging patterns of risk factor make‐up enable subclassification of rheumatoid arthritis

Mil¹,

Huizinga²,

Vries³

et al. 2007

Arthritis & Rheumatism

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Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis

Cited by 479 publications

References 52 publications

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

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

Marked differences in fine specificity and isotype usage of the anti–citrullinated protein antibody in health and disease

Emerging patterns of risk factor make‐up enable subclassification of rheumatoid arthritis

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