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Distribution of TNF‐α, TNF‐R55 and TNF‐R75 in the Rheumatoid Synovial Membrane: TNF Receptors are Localized Preferentially in the Lining Layer; TNF‐α is Distributed Mainly in the Vicinity of TNF Receptors in the Deeper Layers

The expression of TNF‐α and its receptors in the rheumatoid synovial membrane was investigated using immunohistochemistry and immunocytofluorescence. TNF‐α+ cells (< 10% of all cells) were found in all regions, predominantly in sublining and diffuse infiltrates. The highest percentage of TNF‐R+ cells was found in the lining layer (50–90%), with a slight predominance of TNF‐R55. In the sublining, fewer cells expressed TNF‐R (≈ 50%), mostly TNF‐R75. TNF‐R75+ cells were also detectable in diffuse infiltrates and lymphoid aggregates (10–50%). These contained only individual TNF‐R55+ cells. In diffuse infiltrates, there were slightly more TNF‐R55+ cells than in lymphoid aggregates (in both cases < 10%). In sequential sections, TNF‐α+ cells localized mostly in the vicinity of TNF‐R+ cells. Macrophage‐like cells appeared to be the predominant TNF‐R+ cell type. CD3+ T cells in lymphoid aggregates expressed exclusively TNF‐R75. Subsequently, the expression of membrane‐bound TNF‐α, TNF‐R55 and TNF‐R75 was tested by FACS analysis in isolated RA synoviocytes (n = 7 patients). Only four specimens expressed mTNF‐α, and that on a low percentage of cells (2 ± 2.4%; mean ± SD). In contrast, all specimens expressed higher percentages of TNF‐R55 and TNF‐R75 (21 ± 1% and 14 ± 7.1%, respectively). These results demonstrate that: (1) the percentage of cells expressing soluble/transmembrane TNF‐α is greatly outnumbered by the percentage of cells expressing TNF receptors; and (2) TNF‐α‐expressing cells are localized in regions expressing substantial levels of TNF receptors. Therefore, the known pro‐inflammatory and pro‐arthritic effects of TNF‐α are probably mediated by local interactions between the receptors and their soluble and transmembrane ligands.