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Objective: It has previously been shown that the adhesion of lymphocytes to microvascular endothelium mediates lymphocyte extravasation within inflamed synovium. After passing the endothelial barrier, binding of lymphocytes to matrix proteins and synovial lining cells may further lead to synovial membrane hyperplasia and subsequent cartilage destruction. Thus, we have explored the molecular basis of T cell-synovial lining cell interaction in the synovial membrane of patients with rheumatoid arthritis (RA)., Methods: Using an immunohistochemical staining technique and an in vitro frozen section assay we studied the expression and the role of several adhesion molecules in T lymphocyte-synovial lining cell interaction in the inflamed synovial membrane., Results: In RA the macrophage-like (type A) synovial lining cells express high levels of intercellular adhesion molecule 1 [ICAM-1 (CD54)], whereas the fibroblast-like (type B) synovial lining cells predominantly express vascular cell adhesion molecule 1 (VCAM-1), in addition to moderate levels of ICAM-1. Both cell types express low levels of fibronectin. Unstimulated and anti-CD3 stimulated peripheral blood T cells bear the respective ligands lymphocyte function associated antigen 1 [LFA-1 (CD18/11a)], and very late antigen 4 and 5 [VLA-4 (CD29/49d) and VLA-5 (CD29/49e)]. T lymphocytes predominantly bound to type B synovial lining cells. Inhibition studies with monoclonal antibodies revealed that this binding involves the VLA-4/VCAM-1 and VLA-5/fibronectin (FN), but not the VLA-4/CS1 pathway. LFA-1 is also involved in this interaction via its ligand ICAM-1., Conclusion: These results show that the molecular basis of T lymphocyte binding to rheumatoid synovial lining cells is different from that described for T lymphocyte binding to synovial membrane vascular endothelium which involves the VLA-4/VCAM-1 and VLA-4/CS-1 pathways, but not the LFA-1/ICAM-1 pathway.

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

Six patients with rheumatoid factor positive rheumatoid arthritis who had shown a marked symptomatic improvement during four weeks of hypoallergic, artificial diet were studied in greater detail. Placebo controlled rechallenges showed intolerance for specific foodstuffs in four patients. In three of these patients biopsies of both the synovial membrane and of the proximal small intestine were carried out before and during allergen free feeding. In two patients, both with raised serum IgE concentrations and specific IgE antibodies to certain foods, a marked reduction of mast cells in the synovial membrane and proximal small intestine was demonstrated. Although the number of food intolerant patients with RA remains limited and markers of allergic activity are scanty, our observations suggest an underlying immunoallergological mechanism.

Lymphocyte migration to inflammatory sites is an essential factor in the pathogenesis of chronic inflammation. An ensemble of adhesion receptors mediating lymphocyte-endothelial cell recognition and binding are thought to play a crucial role in this process. In the present study, we have explored the molecular basis of lymphocyte adhesion to endothelium in the synovial membrane of patients with rheumatoid arthritis. We established that the very late antigen-4 [VLA-4 (CD49d)] and the vascular cell adhesion molecule-1 (VCAM-1) are important mediators of binding to synovial endothelium of resting and, to a greater extent, of activated T lymphocytes, whereas the leukocyte-function associated antigen-1 [LFA-1 (CD11a/18)]/intercellular adhesion molecule-1 [ICAM-1 (CD54)] pathway is less important in this interaction. In contrast to its prominent role in lymphocyte interaction with endothelium in rheumatoid synovium, the VLA-4/VCAM-1 pathway does not significantly contribute to lymphocyte adhesion to peripheral lymph node high endothelial venule. Thus, the VLA-4/VCAM-1 pathway may be of primary importance in mediating lymphocyte adhesion to inflamed endothelium and in lymphocyte homing to rheumatoid synovium.

Since dendritic cells are believed to play a crucial role in the pathogenesis of rheumatoid arthritis (RA) we studied the microenvironmental relationship of these cells with endothelial cells, lymphocytes and macrophages in the rheumatoid synovial membrane. With the monoclonal antibodies OKIa (MHC Class II determinants), RFD1 and L25 (both specific for "active" human dendritic cells) we identified large numbers of dendritic cells. With the monoclonal antibody HECA 452 [specific for a putative adhesion molecule notably present on high endothelial venules (HEV)], a subset of dendritic cells could be detected. HECA-452 positive dendritic cells were found in 2 basic patterns: (1) associated with small lymphoid cell clusters in the neighborhood of vessels with flat, HECA-452 negative endothelium, (2) at the periphery of dense organoid lymphoid infiltrates, surrounding HECA-452 positive HEV-like vessels. Our data suggest that the influx of HECA-452, L25, RFD1 and MHC Class II positive dendritic cells is an early event in the development of the inflammatory infiltrate found in the rheumatoid synovial membrane. The formation of organoid lymphoplasmacellular infiltrates with high endothelial venules would be secondary to this event.