Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase.

Abstract

OBJECTIVE:

To map the antibody response to human citrullinated alpha-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity with bacterial enolase.

METHODS:

Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated alpha-enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial enolase was investigated by immunoblotting.

RESULTS:

An immunodominant peptide, citrullinated alpha-enolase peptide 1, was identified. Antibodies to this epitope were observed in 37-62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated alpha-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2=0.803, P<0.0001). Affinity-purified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase.

CONCLUSION:

We have identified an immunodominant epitope in citrullinated alpha-enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.

• Authors: Karin Lundberg, Andrew Kinloch, Benjamin A Fisher, Natalia Wegner, Robin Wait, Peter Charles, Ted R Mikuls, Patrick J Venables
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 58 Issue 10 Pg. 3009-19 (Oct 2008) ISSN: 0004-3591 [Print] United States
• PMID: 18821669 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Autoantibodies
• Bacterial Proteins
• Biomarkers, Tumor
• DNA-Binding Proteins
• Tumor Suppressor Proteins
• Citrulline
• ENO1 protein, human
• Phosphopyruvate Hydratase

Topics

• Arthritis, Rheumatoid (immunology, microbiology)
• Autoantibodies (immunology)
• Bacterial Proteins (immunology)
• Bacteroidaceae Infections (immunology)
• Biomarkers, Tumor (chemistry, immunology)
• Case-Control Studies
• Citrulline (chemistry, immunology)
• DNA-Binding Proteins (chemistry, immunology)
• Epitope Mapping
• Female
• Humans
• Male
• Phosphopyruvate Hydratase (chemistry, immunology)
• Porphyromonas gingivalis (enzymology, immunology)
• Tumor Suppressor Proteins (chemistry, immunology)