title: Inhomogeneity of immune cell composition in the synovial sublining: linear mixed modelling indicates differences in distribution and spatial decline of CD68+ macrophages in osteoarthritis and rheumatoid arthritis.
abstract: 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).
  
  
  
  Synovial 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.
  
  
  
  Distribution 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).
  
  
  
  Immune 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.
authors.affiliation: Hiller Research Center Rheumatology at University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Merowingerplatz 1a, 40225, Düsseldorf, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mucke
authors.affiliation: German Diabetes Center, Institute for Biometry and Epidemiology, Düsseldorf, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Hoyer
authors.affiliation: Hiller Research Center Rheumatology at University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Merowingerplatz 1a, 40225, Düsseldorf, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Brinks
authors.affiliation: Hiller Research Center Rheumatology at University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Merowingerplatz 1a, 40225, Düsseldorf, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Bleck
authors.affiliation: Department Orthopaedics, River Rhein Center for Rheumatology at St. Elisabeth Hospital, Meerbusch-Lank, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pauly
authors.affiliation: Hiller Research Center Rheumatology at University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Merowingerplatz 1a, 40225, Düsseldorf, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Hiller Research Center Rheumatology at University Hospital Düsseldorf, Medical Faculty, Heinrich-Heine-University, Merowingerplatz 1a, 40225, Düsseldorf, Germany. stefan.vordenbaeumen@med.uni-duesseldorf.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vordenbäumen
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010003:Osteoarthritis / Q000276:immunology* / Q000473:pathology; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C067980:CD68 antigen, human; D000097382:CD68 Molecule
keywords: CD68; Macrophages; Osteoarthritis; Rheumatoid arthritis; Sublining layer; Synovitis score