Identification of the epidermal growth factor-TM7 receptor EMR2 and its ligand dermatan sulfate in rheumatoid synovial tissue.
OBJECTIVE
EMR2 and CD97 are closely related members of the epidermal growth factor (EGF)-TM7 family of adhesion class 7-span transmembrane (TM7) receptors. Chondroitin sulfates (CS) have recently been identified as ligands for EMR2 and CD97. CS have been implicated in the pathogenesis of rheumatoid arthritis (RA). We undertook this study to determine the expression of EMR2 and the distribution of EMR2 and CD97 ligands within RA synovial tissue (ST).


METHODS
ST samples were obtained by arthroscopy from 19 patients with RA, 13 patients with inflammatory osteoarthritis (OA), and 13 patients with reactive arthritis (ReA). Immunohistochemistry was performed with a monoclonal antibody against EMR2, and stained STs were analyzed by digital image analysis. Coexpression of EMR2 with cell lineage- and activation-specific markers was determined by double immunofluorescence microscopy. To evaluate the expression of EMR2 and CD97 ligands in RA synovium, binding assays were performed using EMR2- and CD97-specific multivalent fluorescent probes.


RESULTS
EMR2 expression in the synovial sublining was found to be significantly higher in RA patients compared with OA and ReA control patients. Most EMR2+ cells were macrophages and dendritic cells expressing costimulatory molecules and tumor necrosis factor alpha. Dermatan sulfate was shown to be the ligand of the largest isoforms of EMR2 and CD97 in rheumatoid synovium. In addition, the smaller isoforms of CD97, but not those of EMR2, bound CD55 on fibroblast-like synoviocytes.


CONCLUSIONS
The EGF-TM7 receptors EMR2 and CD97 are abundantly expressed on myeloid cells in ST of RA patients where their cognate ligands dermatan sulfate and CD55 are detected. These results suggest that these interactions may facilitate the retention of activated macrophages in the synovium.
Kop
Else N
EN
Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Kwakkenbos
Mark J
MJ
Teske
Gwendoline J D
GJ
Kraan
Maarten C
MC
Smeets
Tom J
TJ
Stacey
Martin
M
Lin
Hsi-Hsien
HH
Tak
Paul P
PP
Hamann
Jörg
J
D000368:Aged; D015703:Antigens, CD; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D018958:CD55 Antigens / Q000032:analysis; D003871:Dermatan Sulfate / Q000032:analysis*; D004815:Epidermal Growth Factor / Q000032:analysis*; D005260:Female; D005456:Fluorescent Dyes; D006801:Humans; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D008857:Microscopy, Interference; D008875:Middle Aged; D010003:Osteoarthritis / Q000378:metabolism; D000091402:Prohibitins; D043562:Receptors, G-Protein-Coupled / Q000032:analysis*; D013583:Synovial Membrane / Q000737:chemistry*
C412456:ADGRE2 protein, human; C095004:ADGRE5 protein, human; C428324:ADGRL4 protein, human; D015703:Antigens, CD; D018958:CD55 Antigens; D005456:Fluorescent Dyes; D008024:Ligands; D008562:Membrane Glycoproteins; C000717331:PHB2 protein, human; D000091402:Prohibitins; D043562:Receptors, G-Protein-Coupled; D003871:Dermatan Sulfate; D004815:Epidermal Growth Factor