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Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells
Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, S-17176 Stockholm, Sweden..
Radboud Univ Nijmegen, Dept Biomol Chem, Radboud Inst Mol Life Sci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Inst Mol & Mat, Nijmegen, Netherlands..
Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, S-17176 Stockholm, Sweden..
Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, S-17176 Stockholm, Sweden..
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2016 (English)In: ARTHRITIS RESEARCH & THERAPY, ISSN 1478-6354, Vol. 18, article id 284Article in journal (Refereed) Published
Abstract [en]

Background: Antibodies against citrullinated proteins (ACPA) are common in patients with rheumatoid arthritis (RA). ACPA can appear before disease onset and target many self-antigens. Citrullinated fibrin/fibrinogen represents a classical ACPA target antigen, and mass spectrometry of RA synovial fluid reveals elevated citrullinated (cit) fibrinogen (Fib) peptides compared to non-RA controls. We investigated the extent to which these less-studied peptides represent autoantibody targets and sought to visualize the corresponding cit-Fib-reactive B cells in RA patients. Methods: An in-house ELISA was established against four cit-Fib alpha-subunit peptides (cit-Fib alpha-35; cit-Fib alpha-216,218; cit-Fib alpha-263,271 and cit-Fib alpha-425,426) and serum from patients with established RA (n = 347) and disease controls with psoriatic arthritis (PsA) or ankylosing spondylitis (AS) (n = 236) were analyzed. RA patients were genotyped for HLA-DR alleles, PTPN22 R620W and screened for anti-CCP2 and cit-Fib protein antibodies. The cit-Fib peptides were also used to assemble antigen tetramers to identify cit-Fib-reactive B cells in peripheral blood by flow cytometry. Results: The frequencies of autoantibodies against different cit-Fib epitopes in RA patients compared to PsA/AS patients were: cit-Fib alpha-35 (RA 20%, vs PsA/AS 1%); cit-Fib alpha-216,218 (13% vs 0.5%); cit-Fib alpha-263,271 (21% vs 0.5%) and cit-Fib alpha-425,426 (17% vs 1%). The presence of autoantibodies against these peptides was associated with presence of anti-CCP2 and anti-cit-Fib protein antibodies. No association was found between HLA-DR shared epitope and antibodies to the different cit-Fib peptides. However, association was observed between the PTPN22 risk allele and positivity to cit-Fib alpha-35 and cit-Fib alpha-263,271. B cells carrying surface Ig reactive to these cit-Fib peptides were found in RA peripheral blood and these tend to be more common in PTPN22 risk allele carriers. Conclusions: Our data show that several cit-Fib peptides are targeted by autoantibodies in RA, but not in PsA/AS, implicating that these are not due to arthritis but more specific for RA etiology. The RA-associated anti-cit protein response is broad with many parallel immune responses. The association between cit-Fib autoantibodies and the PTPN22 R620W risk allele supports the hypothesis of altered B cell regulation, such as autoreactive B cells evading tolerance checkpoints.

Place, publisher, year, edition, pages
2016. Vol. 18, article id 284
Keywords [en]
Rheumatoid arthritis, Autoantibodies, Fibrinogen, ACPA, PTPN22
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:uu:diva-313542DOI: 10.1186/s13075-016-1181-0ISI: 000390276200006OAI: oai:DiVA.org:uu-313542DiVA, id: diva2:1070101
Funder
Swedish Research CouncilSwedish Rheumatism AssociationAvailable from: 2017-01-31 Created: 2017-01-20 Last updated: 2018-02-27Bibliographically approved

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