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BiP (heavy chain binding protein) is the major chaperone of the endoplasmic reticulum that interacts transiently with most of the proteins of the secretory pathway and assists in their folding. BiP's function under stress conditions is essential for cell viability and constitutively increasing or decreasing the BiP levels is detrimental to cell growth or to survival. Here, we present the RA autoantigen formerly designated "p68" as identical to BiP and that autoreactivity against BiP is a specific feature of RA.
p68 was isolated and proven to be identical to BiP by two different approaches (Edman sequencing and MALDI-TOF mass spectrometry). Using tissue sections, BiP has been shown to be overexpressed in the RA as compared to the OA joint. Applying immunoblots, BiP-reactive autoantibodies were present in 63% of 400 RA patients, in 7% of 200 patients with other rheumatic diseases and in 1 of 150 healthy individuals. In patients with early arthritis approximately 50% are positive. An ELISA was established to quantify anti-BiP antibodies and the data of 400 RA and 400 control patients will be presented. The majority of RA sera was found reactive with a posttranlationally modified form of BiP and the major epitope was O-linked N-acetylglucosamine.
Furthermore, we present evidence that BiP-specific T cell reactivity is pathogenically altered in RA. Overt BiP-specific T cell reactivity as determined by T cell proliferation assays could be observed in two thirds of patients with RA, but neither in healthy individuals nor in patients with other rheumatic diseases. Blocking anti-HLA-DR antibodies expectedly decreased T cell proliferation indicating the presence of HLA-DR restricted effector T cells.
A subset of RA patients exhibited a BiP-specifically suppressed T cell reactivity. Blocking anti-HLA-DR antibodies in these assays overcame the suppressive effect and allowed an increased proliferation. This argues strongly for the presence of BiP-specific regulatory T cells restricted for HLA-DR and BiP-specific effector T cells restricted for HLA-DP and -DQ in this subset of RA patients. These effects could not be mimicked by blocking anti-IL-10 or anti-TGF-b antibodies, implicating that other factors or also direct cell-cell-contact are required.
Apparently, the healthy immune system views BiP as a component to which autoreactivity is either avoided or tightly regulated. In RA this general principle appears to have lost control. BiP-reactive may serve as a new diagnostic marker in RA, while regulatory T cells may provide means for a specific therapy.