Souichirou Hirata

An immunohistochemical and immunoelectron microscopic study of adhesion molecules in synovial pannus formation in rheumatoid arthritis

To investigate the mechanism of synovial pannus formation in rheumatoid arthritis, immunohistochemical and immunoelectron microscopic studies with monoclonal antibodies against the adhesion molecules, CD54 (ICAM-1), CD 11a (LFA-1), CDw49a (VLA-1), CDw49b (VLA-2), CDw49c (VLA-3), Cdw49d (VLA-4) and CDw49e (VLA-5), were carried out to determine the pattern of distribution of these molecules at the rheumatoid synovial cartilage junction. Treatment with anti-ICAM-1 resulted in membrane staining of most of the macrophages and fibroblasts infiltrating the synovial tissue and bordering the pannus-cartilage junction, suggesting the possibility that ICAM-1 may function to facilitate the adhesion of synovial type A cells bearing ICAM-1 to type B cells of the pannus. ICAM-1-positive macrophages and fibroblasts were often found to be in contact with lymphoid cells, suggesting also that a cellular immune reaction occurs in the formation of the pannus. In addition, VLA-3, VLA-4 and, particularly, VLA-5 were the predominantβ1 integrins expressed by rheumatoid synovial pannus. Since these three integrins all function as fibronectin receptors, it is possible that the fibronectin-rich environment of the rheumatoid cartilage surface effectively traps pannus cells expressing high levels of these molecules. The VLA-5 molecule was found in a pericellular and interterritorial matrix distribution in the present study, strongly suggesting that a recepfor-ligand interaction between VLA-5 and cartilage matrix may occur at the early stage of pannus formation. Furthermore, an increase inβ1 integrin may be necessary for the growth of the pannus and also for the upregulation of the VLA molecules, leading secondarily to increased attachment.

Role of adhesion molecules in the lymphoid cell distribution in rheumatoid synovial membrane

SummaryWe studied the staining pattern of a group of adhesion molecules in the lining layer and lymphocytic infiltrates of the rheumatoid synovial membrane, using monoclonal antibodies against lymphocyte function associated antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), VLA-5, endothelial leucocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1 (ICAM-1). The cells of the the lining layer were strongly ICMA-1 positive and VLA-5 positive, suggesting (1) that ICAM-1 may function to facilitate the adhesion of ICAM-1-bearing type A cells to type B lining cells and (2) that the lining cells may utilize VLA-5 for anchorage to fibronectin at the surface of the synovial membrane. In the lymphocyte-rich and transitional areas, the endothelial cells of the postcapillary venules were both ELAM-1 positive and ICAM-1 positive. ICAM-1 staining was weak in lymphoid aggregates, but strong in the transitional areas, indicating a paucity of ICAM-1-bearing cells in the lymphocyte-rich areas. On the other hand, LFA-1 staining was very strong in the lymphoid aggregates and only moderate in transitional areas. This suggested that the large numbers of T4 cells present in the lymphocyte-rich areas are sufficiently activated to express substantial levels of LFA-1, and also that the LFA-1 molecule is an important receptor for emigration from postcapillary venules. In germinal centre like areas in lymphoid aggregates, most of the cells stained strongly for ICAM-1 and VLA-4, suggesting that the proliferation of B lymphocytes may be facilitated by LFA-1- and VLA4-dependent T and B cell interaction. The VLA molecules stained in the transitional areas may provide appropriate adhesion and anchorage of lymphocytes for the achievement of the variety of immune reactions in which these cells are engaged in these areas.

Rheumatoid pannus formation: synovial cell attachment to the surface of cartilage

As a part of the rheumatoid synovial tissue reaction, proliferating synovial cells penetrate the cartilage in the form of a pannus, and cartilage destruction takes place in the zone between the cells and cartilage. The cellular origin of rheumatoid pannus has been debated by many investigators, and it is accepted that fibroblast proliferation, endothelial cells proliferation and monocyte chemotaxis are probably involved. It has been observed that fibroblasts in the pannus share properties of the fibroblasts and chondrocytes. Mast cell activation is frequently associated with proinflammatory cytokine and metalloprotease expression, suggesting an important role for the mast cell in mediating matrix degradation. The mechanism of interaction of polymorphonuclear leukocytes with immune complexes trapped in rheumatoid cartilage resembles that associated with phenomenon of frustrated phagocytosis. Increased levels of IL-1 in the rheumatoid joint may play an important role in joint destruction by stimulation of pannus formation through induction of synovial cell attachment to the articular surface. Synovial cell attachment to cartilage may be the initial step in pannus formation. We have recently shown that the increased expression of VLA-5 and ICAM-1 at the cartilage-pannus junction may result from the interaction of synovial mononuclear cells with matrix proteins. Therefore, we have raised the possibility that VLA-5 may facilitate the growth of pannus by virtue of its ability to react with fibronectin with resulting proliferation of the synoviocytes of the pannus. Further study will be needed in order to understand the precise mechanism of cartilage erosion and pannus formation in the various arthritic disorders.