The presentation of the immunodominant epitope of HC gp-39 in the context of the RA-associated HLA class II molecules is specific for RA synovium

Objective

Peptide 263–275 is the immunodominant epitope of HC gp-39, a candidate autoantigen in rheumatoid arthritis (RA). The present aim is to analyse HLA-DR SE/HC gp-39^263–275 complexes in synovium of RA patients versus inflammatory controls.

Methods

Synovial biopies were obtained from swollen knee joints in 65 RA patients and 67 controls (30 with spondylarthropathy, 16 with psoriatic arthritis, 10 with crystal-induced arthritis, 7 with osteoarthritis, and 4 with PMR), and from knee joints without synovitis in 9 RA patients. Synovial sections were stained with mAb 12A, which recognizes specifically HLA-DR SE/HC gp-39^263–275 complexes.

Results

mAb 12A revealed mononuclear cells located near lympoid aggregates and positive for CD1a, a marker of dendritic cells. Positive cells were found in 40 of 65 (61.5%) inflamed RA synovia but only in 2 of 30 with spondylarthropathy and 0 of 37 other controls (3.0%) (P < 0.001). In RA, there were no differences between the 12A⁺ and 12A^- patients for disease duration, rheumatoid factor, SE, C-reactive protein, erythrocyte sedimentation rate, nonsteroidal anti-inflammatory drugs, disease-modifying antirheumatic drugs, and corticosteroid. Histological analysis of 12A⁺ versus 12A^- RA synovia indicated a higher score for global inflammation (P = 0.025), CD3 (P = 0.013), CD1a (P = 0.032) and a trend for CD20 (P = 0.066). Accordingly, no 12A⁺ cells were detected in the nine RA knee joints without effusion (6 were SE⁺). HC gp-39 expression was higher in 12A⁺ versus 12A^- samples (P = 0.001). Finally, intracellular citrullinated peptides, which are another specific histological marker for RA synovium, were found in only half of the 12A⁺ samples but also in some 12A^- samples, indicating that the two markers are independent.

Conclusion

HLA-DR SE/HC gp-39^263–275 complexes are frequently detected in inflamed RA synovia but not in inflamed control samples and in noninflamed RA samples. This suggests that dendritic cells actively present the immunodominant epitope of HC gp-39 at the primary site of inflammation in RA. Moreover, the specificity of the staining offers a new and independent tool for the histopathological diagnosis of rheumatoid arthritis.