Multiple antibody reactivities to citrullinated antigens in sera from patients with rheumatoid arthritis: association with HLA-DRB1 alleles.

Abstract

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.

• Authors: O Snir, M Widhe, C von Spee, J Lindberg, L Padyukov, K Lundberg, A Engström, P J Venables, J Lundeberg, R Holmdahl, L Klareskog, V Malmström
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 68 Issue 5 Pg. 736-43 (May 2009) ISSN: 1468-2060 [Electronic] England
• PMID: 18635594 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Autoantigens
• Biomarkers, Tumor
• Collagen Type II
• DNA-Binding Proteins
• HLA-DR Antigens
• HLA-DRB1 Chains
• Immunoglobulin A
• Peptides, Cyclic
• Tumor Suppressor Proteins
• cyclic citrullinated peptide
• Citrulline
• Fibrinogen
• ENO1 protein, human
• Phosphopyruvate Hydratase

Topics

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