ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 912

B-Cell Responses To De Novo Identified Citrullinated Fibrinogen Peptides Are Associated With PTPN22 Risk Allele

Vijay Joshua1, Loes Schobers2, Lena Israelsson3, Johan Rönnelid4, Monika Hansson5, Anca I Catrina6, Ger JM Pruijn2 and Vivianne Malmström7, 1Medicine, Rheumatology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, 2Department of Biomolecular Chemistry, Radboud University, Nijmegen, Netherlands, 3Medicine, Rheumatology unit, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden, 4Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden, 5Rheumatology Unit, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden, 6Rheumatology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden, 7Rheumatology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: B cells in Human and Animal Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Antibodies against citrullinated proteins are common in patients with rheumatoid arthritis (RA) and appear prior to the onset of the disease [1]. Many of the citrullinated epitopes have been identified and studied to varying details. Using an unbiased approach via mass spectrometry, the levels of citrullinated (cit) fibrinogen (Fib) peptides were demonstrated to be elevated in the synovial fluid of RA patients compared to non-RA patients [2]. Here we aim to identify the presence of autoantibodies against these citrullinated peptides.

Methods:

An in-house ELISA was established against 5 citrullinated fibrinogen epitopes (cit-Fib α-35, cit-Fib α-216,218 , cit-Fib α-263,271 , cit-Fib α-425,426  and cit-Fib β-60,72,74) and serum from a cohort of patients with established RA (n=347) and disease controls with psoriatic arthritis (PSA) or ankylosing spondylitis (AS) (n=268) were analyzed. Cut-off for the ELISA was set at 98 percentile, based on reactivity in a cohort of healthy controls (n=152). The RA patients were genotyped with regard to HLA-DR alleles and PTPN22 R620W. The RA cohort has previously been screened for anti-CCP2 antibodies and antibodies against cit-fibrinogen protein (cFib) [3].

Results:

Autoantibodies against the different citrullinated fibrinogen epitopes were present in the following frequencies in the RA patients compared to the PSA/AS patients, cit-Fib α-35 (RA-20%, PSA/AS-2%), cit-Fib α-216,218 (13%, 2%)  , cit-Fib α-263,271 (21%, 2%)  , cit-Fib α-425,426 (17%, 2%)  and cit-Fib β-60,72,74 (4%, 0%).  The presence of autoantibodies against these epitopes was associated with the presence of anti-CCP2 antibodies and antibodies against whole cit-fibrinogen. No genetic association was found between the presence of HLA shared epitope and antibodies to the different cit-Fib epitopes, while an association was observed between the PTPN22 risk allele and positivity to cit-Fib α-35 and cit-Fib α-263,271.

Conclusion:

Fibrinogen is readily citrullinated in the rheumatic joint and our data show that several of the citrullinated epitopes are targeted by autoantibodies in the context of RA, but not in PSA/AS. Our data further emphasizes that the anti-citrulline response is broad with many parallel immune responses. Association between the presence of these autoantibodies with the PTPN22 risk carriers suggest that cit-Fib reactive B-cells would normally be deleted during the B-cell tolerance check points [4].

[1] Rantapää-Dahlqvist S., et. al., Arthritis Rheum. 2003

[2] Raijmakers R., et. al., Arthritis Res Ther. 2012

[3] Snir O., et. al., Arthritis Rheum. 2010

[4] Menard L., et. al., J Clin Invest. 2011

Disclosure:

V. Joshua,
None;

L. Schobers,
None;

L. Israelsson,
None;

J. Rönnelid,
None;

M. Hansson,
None;

A. I. Catrina,
None;

G. J. Pruijn,
None;

V. Malmström,
None.

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