title: Antibodies to proteinase 3 mediate expression of vascular cell adhesion molecule-1 (VCAM-1).
abstract: VCAM-1 was first identified as an adhesion molecule induced on human endothelial cells (HEC) by inflammatory cytokines such as IL-1, tumour necrosis factor (TNF), and lipopolysaccharide (LPS). The molecule binds to a variety of leucocytes, including B cells, T cells, basophils, eosinophils and monocytes. Vascular expression of VCAM-1 has been associated with a number of disease states, including rheumatoid arthritis and vasculitis. The detection of anti-neutrophil cytoplasmic antibodies (ANCA), especially to proteinase 3 (PR3), has become important in the diagnosis of Wegener's granulomatosis (WG) and related vasculitides. Recently we were able to demonstrate a direct effect of anti-PR3 antibodies on neutrophil-endothelial interactions (Blood 1993; 82:1221). Binding of anti-PR3 antibodies to their antigen translocated into the membrane of HEC leads to an enhanced adhesion of neutrophils via induction of E-selectin (Clin Exp Immunol 1993; 94:440). The aim of this study was to investigate the effect of anti-PR3 antibodies on the expression of VCAM-1. HEC were isolated from umbilical vein and cultured on microtitre plates. After preincubation with purified anti-PR3 antibody, purified control antibodies (SS-A, SS-B, RNP) (IgG and F(ab')2 fragments) or different cytokines (controls), VCAM-1 was detected on the surface of unfixed HEC by cyto-ELISA and polymerase chain reaction analysis. Incubation of HEC with anti-PR3 antibodies led to a marked increase of endothelial VCAM-1 expression with a peak after 8 h. Incubation with TNF-alpha also led to maximal VCAM-1 expression after 4-6 h (control). Increased adhesion of T lymphocytes to HEC after binding of anti-PR3 antibodies to their antigen could be confirmed by performing adherence assays. This effect could be inhibited by antibodies to VLA-4. In conclusion, we have been able to show that cytokine-like effects of anti-PR3 antibodies on HEC are not limited to induction of neutrophil adhesion. Anti-PR3 antibodies may thus contribute to the regulation of T lymphocyte migration from the blood by HEC in ANCA-related vasculitides.
authors.affiliation: I. Medical Department, University of Mainz, Germany.
authors.forename: W J
authors.initials: WJ
authors.lastname: Mayet
authors.forename: A
authors.initials: A
authors.lastname: Schwarting
authors.forename: T
authors.initials: T
authors.lastname: Orth
authors.forename: R
authors.initials: R
authors.lastname: Duchmann
authors.forename: K H
authors.initials: KH
authors.lastname: Meyer zum Büschenfelde
mesh_terms: D000906:Antibodies / Q000276:immunology / Q000494:pharmacology*; D001483:Base Sequence; D002448:Cell Adhesion; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data; D053146:Myeloblastin; D012333:RNA, Messenger / Q000096:biosynthesis; D012697:Serine Endopeptidases / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D000906:Antibodies; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D012697:Serine Endopeptidases; D053146:Myeloblastin