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The p205 autoantigen is the strongest stimulatory antigen for T cells known in rheumatoid arthritis (RA). It contains an 11 aminoacid stretch identical to a sequence (278-288) located in the CH2 domain of immunoglobulin G. This domain contains the major epitopes of rheumatoid factors. This study aimed to analyze if the p205-specific T cell responses are also directed against RF epitopes and to analyze the role of p205 in the production of rheumatoid factors in general.
p205 was enriched from synovial fluid as described earlier. p205-derived peptides were chemically synthesized. T cell proliferation assays were performed with cells obtained from RA and control patients and healthy individuals.
Sequencing and mass spectrometry by matrix assisted laser desorption-time of flight (MALDI-TOF) of p205 revealed that it containes sequences with similarity and identity to IgG and other members of the immunoglobulin superfamily. p205 was detected in the synovial membrane of RA patients by antisera specific for p205-derived peptides. Cells staining positive for p205 were also positive for the macrophage marker CD68. p205 staining did never occur in B cell clusters staining positive for CD19 or in T cell infiltrates staining positive for CD3. No B and T cells were detected in the highly p205-positive lining and sublining of the synovial membrane. p205 could react with monoclonal rheumatoid factors (RF). Those RF that reacted also with p205 tended to be of a binding specificity characteristic of RA. Those RF that did not react with p205 tended to be of a binding specificity that is also observed in healthy immunized donors or patients with Waldenström's macroglobulominia.
Synovial fluid (SF), SF-derived p205 and p205-derived peptides were used as antigens in T cell proliferation assays. As control antigens, a mock peptide and PHA were used. SF, p205 and p205-derived peptides stimulated T cells from two thirds of RA patients, but not from patients with other rheumatic diseases or from healthy individuals. SF, p205 and the 11aa p205 peptide with sequence identity to IgG were extremely high stimulators of proliferation in the majority of RA patients and were often in the range of the mitogen PHA. Two other p205-derived peptides were also stimulatory for RA-derived T cells, but to a lesser degree and at a lower frequency of patients. None of these peptides induced T cell proliferation in patients with other rheumatic diseases or healthy individuals. No reactivity was observed with the mock peptide in any of the patients. T cells specific for p205 cocultured in the presence of IgG-specific B cells induced the production of rheumatoid factors upon stimulation with cognate antigen and the 11mer peptide 3. RFs could also be induced upon immunization of rabbits with peptide 3.
p205 is a major target of autoreactive T cells in RA and appears to be a novel member of the immunoglobulin superfamily. It contains an IgG-identical stretch and p205 is targeted by RFs. The IgG-identical peptide 3 stimulates T cells such that they can provide cross-help for RF-secreting B cells in vitro and in vivo. p205 may thus likely be the trigger of RF production in RA and may thus be of pathogenic importance.