ROLE OF ADHESION MECHANISMS IN THE PATHOGENESIS OF CHRONIC SYNOVITIS

The hallmark of many rheumatic conditions, including rheumatoid arthri tis (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 pathogene sis is thought to be immune mediated. There are several reasons to bel ieve that synovial T lymphocytes (S-TL) play a central role both as re gulatory and effector cells in the initiation and perpetuation of the inflammatory process. In early studies, we demonstrated that the major ity of S-TL are of the CD45R0 'memory' phenotype, while CD45RA 'naive' T cells are virtually absent [1,2]. Various mechanisms can be respons ible for such preferential accumulation. In this dissertation. I will present a number of studies. carried out over several years, investiga ting the relative role of adhesion and migration ill the pathogenesis of the CD45R0 accumulation in inflamed tissues. Since the first step i n lymphocyte extravasation is adhesion to endothelium, the ability of purified CD45R0 vs CD45RA T cells to adhere to human umbilical vein en dothelial cells (HUVEC) in vitro was analysed [3]. Second, to examine the migration process itself an in vitro model of cell migration into suction-induced skill blisters raised over delayed-type hypersensitivi ty reactions was developed [4]. Third, the role of tissue-specific hom ing mechanisms in the regulation of T-cell migration into different in flammatory sites was investigated [5]. Finally, the adhesion or T cell s to extracellular matrix (ECM) components, as a mechanism for prefere ntial cell retention in inflamed tissues, was examined [6]. These stud ies demonstrate that the clinical mechanisms leading to CD45R0 lymphoc yte accumulation in chronic inflammatory foci include (a) an increased adhesion to endothelium [3], (b) an increased migratory capacity [4] and (c) an increased adhesion to ECM components [6]. I also present ev idence to suggest that besides these general mechanisms, organ-specifi c homing may be of relevance in determining the selective accumulation of distinct CD45R0 T cells in different inflamed tissues [5].