The stress protein BiP is overexpressed and is a major B and T cell targetin rheumatoid arthritis

Objective. The ubiquitously expressed intracellular protein formerly design ated p68 has been identified as autoantigen at both the antibody and the T cell level in rheumatoid arthritis (RA). Methods. We used 2 independent approaches, Edman degradation and matrix-ass isted laser desorption ionization-time-of-flight mass spectrometry, to char acterize p68, and we compared its features with those of the endoplasmic re ticulum stress protein BiP. Results. In synovial sections from RA patients, BiP was highly overexpresse d as compared with control sections. Under in vitro stress conditions, BiP was found to translocate to the nucleus and the cell surface. BiP-specific autoantibodies were present in 63% of 400 RA patients, in 7% of 200 patient s with other rheumatic diseases, and in none of the healthy subjects. Thus, BiP-specific autoantibodies represent a new diagnostic marker in RA. Furth ermore, we found that BiP-specific T cell reactivity was altered in RA. In healthy individuals and patients with other rheumatic diseases, BiP-reactiv e T cells were undetectable. In RA, overt T cell reactivity to BiP was obse rved or could be induced by specifically blocking antigen presentation to p otentially regulatory T cells. Conclusion. Since overexpression of BiP has been shown to decrease the sens itivity of cells to killing by cytotoxic T cells, BiP overexpression and Bi P-specific autoimmunity may be involved in the pathogenesis of RA.