title: Shedding of large functionally active CD11/CD18 Integrin complexes from leukocyte membranes during synovial inflammation distinguishes three types of arthritis through differential epitope exposure.
abstract: 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.
authors.affiliation: Biophysical Immunology Laboratory, Aarhus University, Aarhus, Denmark.
authors.forename: Louise Carstensen
authors.initials: LC
authors.lastname: Gjelstrup
authors.forename: Thomas
authors.initials: T
authors.lastname: Boesen
authors.forename: Tue Wenzel
authors.initials: TW
authors.lastname: Kragstrup
authors.forename: Annette
authors.initials: A
authors.lastname: Jørgensen
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Klein
authors.forename: Steffen
authors.initials: S
authors.lastname: Thiel
authors.forename: Bent Winding
authors.initials: BW
authors.lastname: Deleuran
authors.forename: Thomas
authors.initials: T
authors.lastname: Vorup-Jensen
mesh_terms: 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
chemical_list: D018845:CD11 Antigens; D018821:CD18 Antigens; D000939:Epitopes; D046912:Multiprotein Complexes; D018799:Intercellular Adhesion Molecule-1