Distribution of TNF-alpha, TNF-R55 and TNF-R75 in the rheumatoid synovial membrane: TNF receptors are localized preferentially in the lining layer; TNF-alpha is distributed mainly in the vicinity of TNF receptors in the deeper layers

The expression of TNF-cr and its receptors in the rheumatoid synovial membr ane was investigated using immunohistochemistry and immunocytofluorescence. TNF-alpha(+) cells (< 10% of all cells) were found in all regions, predomi nantly 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 (approximate to 50%), mostly TNF-R75. TNF-R75(+) cells were also detectable in diffuse infi ltrates and lymphoid aggregates (10-50%). These contained only individual T NF-R55(+) cells. In diffuse infiltrates, there were slightly more TNF-R55() cells than in lymphoid aggregates tin both cases < 10%). In sequential se ctions, TNF-R+ cells localized mostly in the vicinity of TNF-R+ cells. Macr ophage-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-alpha(YI TNF-R55 and TNF-R75 was teste d by FAGS analysis in isolated RA synoviocytes (n = 7 patients). Only four specimens expressed mTNF-alpha, and that on a low percentage of cells (2 +/ - 2.4%; mean +/- SD). In contrast, all specimens expressed higher percentag es of TNF-R55 and TNF-R75 (21 +/- 1% and 14 +/- 7.1%, respectively). These results demonstrate that: (1) the percentage of cells expressing soluble/tr ansmembrane TNF-alpha is greatly outnumbered by the percentage of cells exp ressing TNF receptors; and (2) TNF-alpha-expressing cells are localized in regions expressing substantial levels of TNF receptor;. Therefore, the know n pro-inflammatory and pro-arthritic effects of TNF-alpha are probably medi ated by local interactions between the receptors and their soluble and tran smembrane ligands.