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Antibody responses ...
Antibody responses to de novo identified citrullinated fibrinogen peptides in rheumatoid arthritis and visualization of the corresponding B cells
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- Joshua, Vijay (författare)
- Karolinska Institutet
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- Schobers, Loes (författare)
- Radboud Univ Nijmegen, Dept Biomol Chem, Radboud Inst Mol Life Sci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Inst Mol & Mat, Nijmegen, Netherlands.
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- Titcombe, Philip J. (författare)
- Karolinska Univ Hosp Solna, Karolinska Inst, Dept Med, Rheumatol Unit, S-17176 Stockholm, Sweden.
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- Israelsson, Lena (författare)
- Karolinska Institutet
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- Rönnelid, Johan (författare)
- Uppsala universitet,Klinisk immunologi
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- Hansson, Monika (författare)
- Karolinska Institutet
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- Catrina, Anca I. (författare)
- Karolinska Institutet
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- Pruijn, Ger J. M. (författare)
- Radboud Univ Nijmegen, Dept Biomol Chem, Radboud Inst Mol Life Sci, Nijmegen, Netherlands.;Radboud Univ Nijmegen, Inst Mol & Mat, Nijmegen, Netherlands.
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- Malmstrom, Vivianne (författare)
- Karolinska Institutet
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Karolinska Institutet Radboud Univ Nijmegen, Dept Biomol Chem, Radboud Inst Mol Life Sci, Nijmegen, Netherlands;Radboud Univ Nijmegen, Inst Mol & Mat, Nijmegen, Netherlands. (creator_code:org_t)
- 2016-12-01
- 2016
- Engelska.
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Ingår i: ARTHRITIS RESEARCH & THERAPY. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 18
- Relaterad länk:
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https://uu.diva-port... (primary) (Raw object)
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https://arthritis-re...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
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- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
Nyckelord
- Rheumatoid arthritis
- Autoantibodies
- Fibrinogen
- ACPA
- PTPN22
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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