ROLE OF THE CS1 ADHESION MOTIF OF FIBRONECTIN IN T-CELL ADHESION TO SYNOVIAL-MEMBRANE AND PERIPHERAL LYMPH-NODE ENDOTHELIUM

Objectives-It has previously been shown that the very late antigen-4/v ascular cell adhesion molecule-1 (VLA-4/VCAM-1) pathway functions as a receptor/ligand interaction system mediating the recruitment of activ ated lymphocytes to inflamed synovium of patients with rheumatoid arth ritis. This study was performed to determine whether VLA-4 also affect s lymphocyte adhesion to inflamed synovium through interaction with th e alternatively spliced CSI domain of fibronectin. Methods-The effect of the synthetic peptide CSI on lymphocyte binding to human synovial a nd peripheral lymph node high endothelial venules (HEVs) was measured in an in vitro frozen section assay. Results-In the presence of the CS 1 peptide or antibody to fibronectin, significant inhibition of bindin g was observed (54 and 51% respectively). Blocking with antibody to VC AM-1 yielded inhibition of binding to 46% of the control value. Maximu m inhibition of binding was obtained with a combination of antibody to VCAM-1 and CSI (65%) and with antibody to VLA-4alpha (68%). Blocking the classical fibronectin receptor with antibody to VLA-5alpha gave a slightly lower inhibition at 42%. In normal peripheral lymph nodes, th e synthetic peptide CS1 and antibodies to fibronectin and VLA-5 also p artially inhibited T cell binding to HEVs (45, 47, and 52% respectivel y). Conclusion-These results show that fibronectin mediates lymphocyte -HEV interactions not only through its classical VLA-5 receptor, but a lso through its CS1 adhesion motif in inflamed synovium and peripheral lymph nodes.