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Autoantibodies to the nuclear antigen hnRNP-A2/RA33 are present in sera of RA patients and also in TNFa transgenic (tg) mice which develop severe erosive arthritis similar to human disease. Furthermore, autoreactive T cells have recently been found in peripheral blood of 60% of RA patients suggesting hnRNP-A2/RA33 to be also a major T cell autoantigen.
To investigate the pathway leading to loss of tolerance, expression of hnRNP-A2/RA33 was investigated by immunohistochemistry in synovial tissue derived from patients with RA and osteoarthritis (OA) as well as in joint sections of TNFa tg and control mice. These analyses revealed the antigen to be considerably overexpressed in RA as compared to OA tissue, particularly in macrophages of the lining layer and in fibroblasts of the sublining areas, whereas no or very little expression was observed in areas of lymphocyte infiltration. Remarkably, the antigen was not only located in the nucleus (as in cultured cells) but also abundantly detectable in the cytoplasm. Similar observations were made in TNFa tg animals in which strong hnRNP-A2/RA33 expression could be also observed at cartilage-pannus junctions. Interestingly, anti-A2/RA33 aab were not detectable in 8 animals treated with tissue inhibitor of metalloproteases 1 (TIMP 1) suggesting that metalloproteases may be involved in breakage of tolerance to hnRNP-A2/RA33. To elucidate the biological mechanisms leading to aberrant expression of hnRNP-A2/RA33 peripheral blood monocytes and T lymphocytes as well as cultured synovial fibroblasts and HeLa cells were treated with various stimulating agents including LPS, PHA, anti-CD3, IL-1, TNFa and IFNg or exposed to heat stress. However, none of these stimuli was able to induce upregulation or nucleocytoplasmic translocation of the antigen.
Taken together, these findings suggest that the state of chronic inflammation in the rheumatoid synovium causes aberrant expression of hnRNP-A2/RA33 (and possibly other autoantigens). This may lead to increased uptake and (aberrant) degradation and presentation by macrophages and other antigen presenting cells subsequently activating autoreactive T cells which then may drive or enhance the inflammatory and destructive processes characteristic of RA.