Immunohistochemical aspects of the fibrogenic pathway in nephrogenic systemic fibrosis.
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Nephrogenic systemic fibrosis (NSF) is a rare gadolinium-dependent disorder of the skin and viscera. The aim of this study was to revisit some immunopathologic clues of NSF, including the characterization of glycosaminoglycans, cell tensegrity, and cell proliferation in the dermis. Immunohistochemistry was done using antibodies directed to vimentin, CD34, Factor XIIIa, calprotectin, α-smooth muscle actin, Ulex europaeus agglutinin-1 (UEA-1), and MIB1/Ki67 and to glycosaminoglycans, including CD44 var3, versican, and perlecan. The vimentin+ cell density was markedly increased. The vast majority of them corresponded to CD34+ or Factor XIIIa+ dermal dendrocytes (DD) showing distinct cell tensegrity. CD34+DD were slender, elongated, and usually scattered in the dermis but focally clustered in nodular collections. By contrast, Factor XIIIa+ was plump with squat dendrites showing no evidence for being under mechanical stress. Cells in the vicinity of the microvasculature were rounded and exhibited calprotectin immunoreactivity typical for monocyte/macrophages. The microvasculature highlighted by UEA-1 and α-smooth muscle actin looked unremarkable. The cell proliferation highlighted by the MIB/Ki67 immunoreactivity was unusually high (>20%) in the interstitial stromal cells. Stromal cells enriched in versican were plump, abundant, and seemed interconnected each other by a dense network of dendrites. By contrast, the immunolabeling for perlecan and CD44 var 3 was unremarkable. In conclusion, the cell population involved in NSF seemed phenotypically heterogeneous, and its growth fraction was clearly boosted in the skin. The intracellular load in versican was prominent. The aspect of cell tensegrity did not suggest the influence of mechanical stress putting stromal cells under tension in the dermis.