Multiple antibody reactivities to citrullinated antigens in sera from rheumatoid arthritis patients – association with HLA-DRB1 alleles
Omri Snir 1, Mona Widhe 1, Caroline von Spee 1, Johan Lindberg 2, Leonid Padyukov 1, Karin Lundberg 3, Åke Engström 4, Patrick J Venables 3, Joakim Lundeberg 2, Rikard Holmdahl 5, Lars Klareskog 1 and Vivianne Malmström 1*
1 Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Sweden
2 Department of Gene Technology, AlbaNova University Center, Royal Institute of Technology, Sweden
3 Kennedy Institute of Rheumatology, Imperial College, United Kingdom
4 Uppsala Bimediacal Center, IMBIM, Sweden
5 Medical Inflammation Research, Lund University, Sweden
* To whom correspondence should be addressed. E-mail: vivianne.malmstrom{at}ki.se.
Accepted 21 June 2008
 | Abstract |
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Objective: Autoantibodies to cyclic citrullinated peptides (CCP) are present in the majority of rheumatoid arthritis (RA) patients, and associate with HLA-DRB1 shared epitope (SE) alleles. Here we investigated reactivities to various citrullinated proteins/peptides, which represent potential autoantigens in RA. We studied the relationship between such antibodies as well as their association with genetic variants within HLA-DRB1 SE alleles.
Methods: Sera from 291 patients with established RA and 100 sex and age matched healthy subjects were included in this study. Sera were first analyzed for presence of anti-CCP antibodies and further for IgG and IgA antibodies toward candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type-II collagen (C1III). Antibody specificity was confirmed by cross reactivity tests. HLA-DR genotyping was performed.
Results: 72% of the RA patients were anti-CCP positive. Amongst the candidate autoantigens examined, IgG antibodies to citrullinated-fibrinogen were found in 66% of patients’ sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1III. These antibodies were mainly seen in the anti-CCP-positive patient group, they were specific for their respective antigen and displayed limited cross-reactivity. IgA responses were also detected, but less frequent than IgG. Anti-CCP as well as anti citrullinated protein antibodies were associated with the HLA-DRB1*04 rather than with HLA-DRB1*01.
Conclusions: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multi-reactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.
