Detection of major histocompatibility complex/human cartilage gp-39 complexes in rheumatoid arthritis synovitis as a specific and independent histologic marker.

Abstract

Peptide 263-275 is the immunodominant epitope of human cartilage (HC) gp-39, a candidate autoantigen in rheumatoid arthritis (RA). We recently generated and characterized a monoclonal antibody (mAb) called 12A, which is directed against HLA-DR4/HC gp-39(263-275) complexes and inhibits specific T cell responses in vitro. The aim of the present study was to analyze whether presentation of the immunodominant epitope of HC gp-39 by shared epitope-positive synovial dendritic cells is a specific event in the development of chronic synovial inflammation in RA. Staining with mAb 12A was performed on synovium obtained from clinically swollen joints in 65 patients with RA and 67 non-RA controls and from joints without clinical effusion in 9 additional patients with RA. Monoclonal antibody 12A staining was observed in the synovium of 40 of the 65 patients with RA. Histologically, expression of HC gp-39, lymphoid aggregates, CD3, and CD1a as well as the global inflammation score were higher in mAb 12A-positive RA synovium than in mAb 12A-negative synovium, indicating a follicular synovitis in these samples. Accordingly, mAb 12A stained dendritic cells in the close vicinity of lymphoid aggregates. No mAb 12A staining was detected in synovium obtained from RA joints without effusion. Clinically, there were no correlations between mAb 12A staining and clinical or biologic parameters in RA. However, positive staining was observed in 61.5% of the inflamed RA synovial samples compared with only 3.0% of the control samples (P < 0.001). This mAb 12A staining was not related to intracellular citrullinated peptides, which are another specific histologic marker for RA. Presentation by synovial dendritic cells of the immunodominant epitope of HC gp-39, in the context of the shared epitope, is associated with characteristic histologic features of follicular synovitis and is highly specific for RA. This suggests a contribution to the autoimmune-related tissue inflammation and provides a new and independent tool for the immunopathologic diagnosis of RA.