Abstract
BackgroundInhomogeneity of immune cell distribution in the synovial sublining layer was analyzed in order to improve our mechanistic understanding of synovial inflammation and explore potential refinements for histological biomarkers in rheumatoid arthritis (RA) and osteoarthritis (OA).MethodsSynovial tissue of 20 patients (11 RA, 9 OA) was immunohistochemically stained for macrophages (CD68), synovial fibroblasts (CD55), T cells (CD3), plasma cells (CD38), endothelial cells (vWF) and mast cells (MCT). The synovial sublining layer was divided into predefined adjacent zones and fractions of the stained area (SA) were determined by digital image analysis for each cell marker.ResultsDistribution of CD68, CD55, CD38 and MCT staining of the sublining area was heterogeneous (Friedman ANOVA p < 0.05). The highest expression for all markers was observed in the upper layer close to the lining layer with a decrease in the middle and lower sublining. The SA of CD68, CD55 and CD38 was significantly higher in all layers of RA tissue compared to OA (p < 0.05), except the CD38 fraction of the lower sublining. Based on receiver operating characteristics analysis, CD68 SA of the total sublining resulted in the highest area under the curve (AUC 0.944, CI 95 % 0.844–1.0, p = 0.001) followed by CD68 in the upper and middle layer respectively (both AUC 0.933, CI 95 % 0.816–1.0, p = 0.001) in both RA and OA. Linear mixed modelling confirmed significant differences in the SA of sublining CD68 between OA and RA (p = 0.0042) with a higher concentration of CD68+ towards the lining layer and more rapid decline towards the periphery of the sublining in RA compared to OA (p = 0.0022).ConclusionsImmune cells are inhomogeneously distributed within the sublining layer. RA and OA tissue display differences in the number of CD68 macrophages and differences in CD68 decline within the synovial sublining.
Highlights
Inhomogeneity of immune cell distribution in the synovial sublining layer was analyzed in order to improve our mechanistic understanding of synovial inflammation and explore potential refinements for histological biomarkers in rheumatoid arthritis (RA) and osteoarthritis (OA)
Immune cells are inhomogeneously distributed within the sublining layer In order to assess cellular distribution within the sublining layer, immunohistochemistry was applied to stain for macrophages (CD68), synovial fibroblasts (CD55), T cells (CD3), plasma cells (CD38), endothelial cells and mast cells (MCT) (Fig. 1)
We demonstrate a strikingly inhomogeneous distribution of most immune cells and fibroblasts within the sublining layer of both RA and OA tissue with a clear tendency of macrophages (CD68), synovial fibroblasts (CD55), plasma cells (CD38), mast cells (MCT) and endothelial cells
Summary
Inhomogeneity of immune cell distribution in the synovial sublining layer was analyzed in order to improve our mechanistic understanding of synovial inflammation and explore potential refinements for histological biomarkers in rheumatoid arthritis (RA) and osteoarthritis (OA). Histological analysis of the synovial membrane is a powerful tool for the investigation of pathological changes in rheumatoid arthritis (RA) in order to elucidate the pathogenic mechanisms involved in the disease [1]. CD68-positive macrophages in the sublining layer have repeatedly been shown to be one of the best activity markers for RA [6, 7]. Further cells are of major interest in synovial biopsies: synovial fibroblasts are considered key players in the pathogenesis of rheumatoid arthritis [8]. Mast cells have been identified to modulate B cells and produce proinflammatory cytokines in RA [12, 13] whereas endothelial cells function as a marker for increased angiogenesis in inflamed tissue [14]
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