EXPRESSION AND FUNCTIONAL-SIGNIFICANCE OF AN ACTIVATION-DEPENDENT EPITOPE OF THE BETA-1 INTEGRINS IN CHRONIC INFLAMMATORY DISEASES

The avidity of VLA integrins for their ligands can be increased by the ir transition to an active conformational state. This conformational c hange can be detected with a novel monoclonal antibody (mAb), termed 1 5/7, that recognizes an activation-dependent conformational epitope on the common beta 1 polypeptide of different VLA alpha beta integrins. In an attempt to understand the possible role of the active conformati onal state of beta 1 integrins in vivo, we first investigated the expr ession of 15/7 epitope on T lymphocytes from patients with chronic inf lammatory joint diseases. An enhanced expression of the 15/7 epitope w as found in the synovial fluid (SF)T lymphocytes from these patients a s compared to their peripheral blood (PB)T cells. The effect of differ ent cytokines on the appearance of the 15/7 activation epitope in PB T lymphocytes was subsequently analyzed; interferon-gamma, interleukin- 2 and, to a lower extent, tumor necrosis factor-alpha were able to ind uce an increased expression of the 15/7 epitope. This enhanced 15/7 ex pression correlated with a higher binding ability to fibronectin of cy tokine-activated T cells. The presence of this activation epitope was detected in a small proportion of T lymphocytes scattered within infla mmatory foci of synovial membrane from rheumatoid arthritis and thyroi d glands from Hashimoto's chronic thyroiditis. We then analyzed the po ssible role of 15/7 epitope expression on eel adhesion in vitro. Immun ofluorescence studies showed that the 15/7 epitope displayed a spot-li ke distribution, selectively decorating adhesive contacts of U-937 mye lomonocytic cells attached to the 80 kDa proteolytic fragment of fibro nectin (FN80). Furthermore, the anti-beta 1 15/7 mAb was able to induc e both T lymphocyte, Jurkat and U-937 cellular binding and spreading o n FN80. Altogether these results indicate that an activated conformati on of beta 1 integrins is detected in vivo in lymphocyte infiltrates f rom chronic inflammatory conditions. The active conformations of beta 1 integrins are regulated by physiologic mediators such as cytokines, play an important role in cellular attachment and spreading, and appea r to be involved in the development of inflammatory processes.