title: Expression and functional significance of an activation-dependent epitope of the beta 1 integrins in chronic inflammatory diseases.
abstract: The avidity of VLA integrins for their ligands can be increased by their transition to an active conformational state. This conformational change can be detected with a novel monoclonal antibody (mAb), termed 15/7, that recognizes an activation-dependent conformational epitope on the common beta 1 polypeptide of different VLA alpha beta 1 integrins. In an attempt to understand the possible role of the active conformational state of beta 1 integrins in vivo, we first investigated the expression of 15/7 epitope on T lymphocytes from patients with chronic inflammatory joint diseases. An enhanced expression of the 15/7 epitope was found in the synovial fluid (SF) T lymphocytes from these patients as compared to their peripheral blood (PB) T cells. The effect of different 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 induce an increased expression of the 15/7 epitope. This enhanced 15/7 expression correlated with a higher binding ability to fibronectin of cytokine-activated T cells. The presence of this activation epitope was detected in a small proportion of T lymphocytes scattered within inflammatory foci of synovial membrane from rheumatoid arthritis and thyroid glands from Hashimoto's chronic thyroiditis. We then analyzed the possible role of 15/7 epitope expression on cell adhesion in vitro. Immunofluorescence studies showed that the 15/7 epitope displayed a spot-like distribution, selectively decorating adhesive contacts of U-937 myelomonocytic cells attached to the 80 kDa proteolytic fragment of fibronectin (FN80). Furthermore, the anti-beta 1 15/7 mAb was able to induce both T lymphocyte, Jurkat and U-937 cellular binding and spreading on FN80. Altogether these results indicate that an activated conformation of beta 1 integrins is detected in vivo in lymphocyte infiltrates from 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 appear to be involved in the development of inflammatory processes.
authors.affiliation: Servicio de Inmunología, Hospital de la Princesa, Universidad Autónoma, Madrid, Spain.
authors.forename: A G
authors.initials: AG
authors.lastname: Arroyo
authors.forename: R
authors.initials: R
authors.lastname: García-Vicuña
authors.forename: M
authors.initials: M
authors.lastname: Marazuela
authors.forename: T A
authors.initials: TA
authors.lastname: Yednock
authors.forename: R
authors.initials: R
authors.lastname: González-Amaro
authors.forename: F
authors.initials: F
authors.lastname: Sánchez-Madrid
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D019012:Integrin beta1; D016023:Integrins / Q000096:biosynthesis* / Q000737:chemistry / Q000276:immunology; D009928:Organ Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D000939:Epitopes; D019012:Integrin beta1; D016023:Integrins