The Michael Mason Prize Essay 1996. Role of adhesion mechanisms in the pathogenesis of chronic synovitis.

The hallmark of many rheumatic conditions, including rheumatoid arthritis (RA) and other seronegative inflammatory arthropathies (OIA), is a persistent inflammatory process that mainly affects synovial joints. Although the aetiology of the synovitis remains elusive, the pathogenesis is thought to be immune mediated. There are several reasons to believe that synovial T lymphocytes (S-TL) play a central role both as regulatory and effector cells in the initiation and perpetuation of the inflammatory process. In early studies, we demonstrated that the majority of S-TL are of the CD45RO 'memory' phenotype, while CD45RA 'naive' T cells are virtually absent. Various mechanisms can be responsible for such preferential accumulation. In this dissertation, I will present a number of studies, carried out over several years, investigating the relative role of adhesion and migration in the pathogenesis of the CD45RO accumulation in inflamed tissues. Since the first step in lymphocyte extravasation is adhesion to endothelium, the ability of purified CD45RO vs CD45RA T cells to adhere to human umbilical vein endothelial cells (HUVEC) in vitro was analysed. Second, to examine the migration process itself, an in vivo model of cell migration into suction-induced skin blisters raised over delayed-type hypersensitivity reactions was developed. Third, the role of tissue-specific homing mechanisms in the regulation of T-cell migration into different inflammatory sites was investigated. Finally, the adhesion of T cells to extracellular matrix (ECM) components, as a mechanism for preferential cell retention in inflamed tissues, was examined. These studies demonstrate that the critical mechanisms leading to CD45RO lymphocyte accumulation in chronic inflammatory foci include (a) an increased adhesion to endothelium, (b) an increased migratory capacity and (c) an increased adhesion to ECM components. I also present evidence to suggest that besides these general mechanisms, organ-specific homing may be of relevance in determining the selective accumulation of distinct CD45RO T cells in different inflamed tissues.