Responses of lymphocytes of patients with rheumatoid arthritis to IgG modified by oxygen radicals or peroxynitrite.

OBJECTIVE

We have previously demonstrated the presence of IgG aggregates modified by oxygen radicals (chlorinated IgG [Cl-IgG]) and peroxynitrite (nitrated IgG [N-IgG]) in synovial fluid of patients with rheumatoid arthritis (RA). A possible explanation for the longstanding chronic inflammatory process in RA is the establishment of an immune response to autoantigens. This study was undertaken to examine whether a T cell response to oxidatively modified IgG contributes to the inflammation in RA.

METHODS

We studied in vitro lymphocyte proliferation and interleukin 2 (IL-2) secretion in response to a common antigen (mumps), N-IgG, Cl-IgG, and heat-aggregated IgG (H-IgG) (control) in 15 normal blood donors and 16 RA patients not receiving immunosuppressive drugs.

RESULTS

The responses of RA lymphocytes to mumps antigen were significantly lower that those in controls (mean +/- SEM 2,577 +/- 217 versus 6,367 +/- 365 counts per minute/well; P < 0.02). However, whereas in normal donors the cell responses to N-IgG and Cl-IgG were not significantly different than responses to H-IgG (N-IgG/H-IgG ratio 1.2 +/- 0.2, Cl-IgG/H-IgG 1.5 +/- 0.2), the RA lymphocyte responses to N-IgG and Cl-IgG were significantly higher than the responses to H-IgG (N-IgG/H-IgG 7.4 +/- 2.5, Cl-IgG/H-IgG 4.8 +/- 1.2). When ratios in RA cells were compared with normal cell responses as a group, there was a significant difference for both N-IgG (P < 0.017) and Cl-IgG (P < 0.014). When selected normal and RA lymphocyte culture supernatants were assayed for IL-2 secretion, the increase in IL-2 never exceeded 2-fold in normal cell cultures incubated with any of the IgG compared with unstimulated cultures, whereas responses of RA cells, particularly those incubated with N-IgG, were increased (range 2.6-15.7-fold) compared with unstimulated controls.

CONCLUSION

These results suggest that in RA there are circulating T cells that are responsive to oxidatively modified IgG, a possible pathogenic mechanism contributing to the chronic inflammatory process within the inflamed joint.