Fine specificity of the anti–citrullinated protein antibody response is influenced by the shared epitope alleles

Verpoort, Kirsten N; Cheung, King‐Loong; Ioan‐Facsinay, Andreea; Mil, Annette H M van der Helm-van; Vries-Bouwstra, Jeska K de; Allaart, Cornelia F; Drijfhout, Jan W.; Vries, R. R. P. De; Breedveld, F. C.; Huizinga, Tom W J; Pruijn, Ger J. M.; Toes, René E. M.

doi:10.1002/art.23127

Cited by 116 publications

(133 citation statements)

References 17 publications

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“…Therefore, we subsequently confirmed our observations using another strategy as well by calculating the cut-off as the mean plus two times SD of the anti-Ca-FCS response in controls. This cut-off was applied to the data of the RA patients as was also used before (29). The association with radiological progression of anti-CarP IgG in ACPA-negative RA remains significant, albeit with a lower level of significance (P = 0.001).…”

Section: Resultsmentioning

confidence: 99%

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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.

484

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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Section: Resultsmentioning

confidence: 99%

“…After washing, Fib peptides containing either an arginine, citrulline, homocitruline, or lysine (Fig. 3A) (29) were incubated at 10 μg/mL in 100 μL PTB for 1 h at room temperature. Next, the reactivity of antibodies reactive to these antigens was detected as described above.…”

Section: Methodsmentioning

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.

484

577

View full text Add to dashboard Cite

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“…The following linear citrullinated peptides and their native counterparts were used for fine specificity studies: C2 (vim) (STCit SVS SSS YCitCit MFG G) (22) and C3 (vim) (VYA TCitS SAV CitLCit SSV P) (23) derived from human vimentin, C4 (fib) (NEE GFF SACit GHR PLD KK) (23) and C5 (fib) (FLA EGG GVCit GPR VVE RH) (unpublished data) derived from human fibrinogen, and C6 (enolase) (KIH ACitE IFD SCitG NPT V) (24) derived from human non-neuronal enolase. All synthetic peptides were coated on streptavidin-coated plates (Fisher, Winnepeg, Manitoba, Canada) via a C-terminal long-chain biotin.…”

Section: Methodsmentioning

confidence: 99%

“…All synthetic peptides were coated on streptavidin-coated plates (Fisher, Winnepeg, Manitoba, Canada) via a C-terminal long-chain biotin. Detection of antibodies recognizing these peptides was performed as previously described (23).…”

Section: Methodsmentioning

confidence: 99%

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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“…Subsequently, the specificity of the ACPA response was studied in patients with RA, by measuring serum antibodies against a citrullinated peptide derived from vimentin and antibodies against a citrullinated fibrinogen peptide. In 2 independent cohorts, the SE alleles predisposed to the development of antibodies against citrullinated vimentin and not the development of antibodies against citrullinated fibrinogen (28,29). These data indicate that SE alleles act as "classic" immune response genes in the ACPA response, because they influence both the magnitude and the specificity of this RA-specific antibody response.…”

Section: Hla and Acpasmentioning

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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Fine specificity of the anti–citrullinated protein antibody response is influenced by the shared epitope alleles

Cited by 116 publications

References 17 publications

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

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

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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