Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure.
CD18 integrins are adhesion molecules expressed on the cell surface of leukocytes and play a central role in the molecular mechanisms supporting leukocyte migration to zones of inflammation. Recently, it was discovered that CD11a/CD18 is shed from the leukocyte surface in models of inflammation. In this study, we show that shedding of human CD11/CD18 complexes is a part of synovial inflammation in rheumatoid arthritis and spondyloarthritis but not in osteoarthritis. In vivo and in vitro data suggest that the shedding is driven by TNF-α, which links the process to central events in the inflammatory response. The shed complexes contain multiple heterodimers of CD11/CD18, are variable in size, and differ according to the type of synovial inflammation. Furthermore, the differential structures determine the avidity of binding of the complexes to the ICAM-1. With the estimated concentrations of CD11/CD18 in plasma and synovial fluid a significant coverage of binding sites in ICAM-1 for CD18 integrins is expected. Based on cell adhesion experiments in vitro, we hypothesize that the large soluble complexes of CD11/CD18 act in vivo to buffer leukocyte adhesion by competing with the membrane-bound receptors for ICAM-1 binding sites. As reported here for synovial inflammation changes in the concentration or structure of these complexes should be considered as likely contributors to disease activity.
Gjelstrup
Louise Carstensen
LC
Biophysical Immunology Laboratory, Aarhus University, Aarhus, Denmark.
Boesen
Thomas
T
Kragstrup
Tue Wenzel
TW
Jørgensen
Annette
A
Klein
Nigel J
NJ
Thiel
Steffen
S
Deleuran
Bent Winding
BW
Vorup-Jensen
Thomas
T
D000328:Adult; D001168:Arthritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018845:CD11 Antigens / Q000276:immunology / Q000378:metabolism*; D018821:CD18 Antigens / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D000939:Epitopes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism; D013583:Synovial Membrane / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D018845:CD11 Antigens; D018821:CD18 Antigens; D000939:Epitopes; D046912:Multiprotein Complexes; D018799:Intercellular Adhesion Molecule-1