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BACKGROUND: Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles. OBJECTIVE: To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles. METHODS: Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type II collagen (C1(III)). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed. RESULTS: 72% of patients with RA were anti-CCP positive. Among 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 C1(III). 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 frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles. CONCLUSIONS: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.

Original publication

DOI

10.1136/ard.2008.091355

Type

Journal article

Journal

Annals of the rheumatic diseases

Publication Date

05/2009

Volume

68

Pages

736 - 743

Addresses

Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Karolinska Institute, Solna, Stockholm, Sweden.

Keywords

Humans, Arthritis, Rheumatoid, Peptides, Cyclic, Collagen Type II, Phosphopyruvate Hydratase, Citrulline, Fibrinogen, Immunoglobulin A, DNA-Binding Proteins, Tumor Suppressor Proteins, Tumor Markers, Biological, Autoantibodies, HLA-DR Antigens, Autoantigens, Cross Reactions, Genotype, Alleles, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Young Adult, HLA-DRB1 Chains