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Antibodies to carbamylated alpha-enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies
Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
Karolinska Inst, Inst Environm Med, Cardiovasc Epidemiol, S-10401 Stockholm, Sweden..
Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden..
Karolinska Inst, Dept Med, Rheumatol Unit, Stockholm, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem, Stockholm, Sweden..
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2016 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, 96Article in journal (Refereed) PublishedText
Abstract [en]

Background: In addition to anti-citrullinated protein antibodies (ACPAs), antibodies targeting carbamylated (i.e., homocitrullinated) proteins (anti-CarP antibodies) have been described in rheumatoid arthritis (RA). However, the extent to which anti-CarP antibodies are truly distinct from ACPA remains unclear, and few studies have focused on specific autoantigens. Here, we examine cross-reactivity between ACPA and anti-CarP antibodies, in the context of the candidate autoantigen a-enolase. Methods: Cross-reactivity was examined by immunoblotting of citrullinated and carbamylated proteins using purified ACPA; and by peptide absorption experiments, using the citrullinated alpha-enolase peptide CEP-1 and a homocitrulline-containing version (carb-CEP-1) in ELISA. The population-based case-control cohort EIRA (n = 2836 RA; 373 controls) was screened for reactivity with CEP-1 and carb-CEP-1, using the ISAC multiplex array. Associations between anti-CarP antibodies, smoking and genetic risk factors were analysed using unconditional logistic regression models. Differences in antibody levels were investigated using the Mann-Whitney U test. Results: Affinity-purified ACPA was found to bind carbamylated proteins and homocitrulline-containing peptides, demonstrating definitive cross-reactivity between ACPA and anti-CarP antibodies. Anti-carb-CEP-1 reactivity in EIRA was almost exclusively confined to the CEP-1-positive subset, and this group of RA patients (21 %) displayed a particularly strong ACPA response with marked epitope spreading. The small RA subset (3 %) with homocitrulline reactivity in the absence of citrulline reactivity did not associate with smoking or risk genes, and importantly had significantly lower anti-carb-CEP-1 antibody levels. Conclusion: Our data presented herein cast doubt on the specificity of anti-CarP antibodies in RA, which we posit may be a subset of cross-reactive ACPA.

Place, publisher, year, edition, pages
2016. Vol. 18, 96
Keyword [en]
Anti-citrullinated protein antibodies, Anti-carbamylated protein antibodies, Rheumatoid arthritis, Cross-reactivity
National Category
Rheumatology and Autoimmunity
URN: urn:nbn:se:uu:diva-297792DOI: 10.1186/s13075-016-1001-6ISI: 000375639700001PubMedID: 27145822OAI: oai:DiVA.org:uu-297792DiVA: diva2:943549
Swedish Research CouncilSwedish Rheumatism AssociationEU, FP7, Seventh Framework Programme, FP7-Health-2013-306029
Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2016-06-28Bibliographically approved

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Mathsson-Alm, LindaRönnelid, Johan
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