title: LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds.
abstract: Recently, we reported a rare leukocyte adhesion deficiency (LAD) associated with severe defects in integrin activation by chemokine signals, despite normal ligand binding of leukocyte integrins.(1) We now report that the small GTPase, Rap1, a key regulator of inside-out integrin activation is abnormally regulated in LAD Epstein-Barr virus (EBV) lymphocyte cells. Both constitutive and chemokine-triggered activation of Rap1 were abolished in LAD lymphocytes despite normal chemokine signaling. Nevertheless, Rap1 expression and activation by phorbol esters were intact, ruling out an LAD defect in Rap1 guanosine triphosphate (GTP) loading. The very late antigen 4 (VLA-4) integrin abnormally tethered LAD EBV lymphocytes to its ligand vascular cell adhesion molecule 1 (VCAM-1) under shear flow due to impaired generation of high-avidity contacts despite normal ligand binding and intact avidity to surface-bound anti-VLA-4 monoclonal antibody (mAb). Thus, a defect in constitutive Rap1 activation results in an inability of ligand-occupied integrins to generate high-avidity binding to ligand under shear flow. This is a first report of an inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function, we herein term it "LAD-III."
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel. ronalon@wicc.weizmann.ac.il
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kinashi
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Maya
authors.initials: M
authors.lastname: Sokolovsky-Eisenberg
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Chisato
authors.initials: C
authors.lastname: Tanaka
authors.forename: Revital
authors.initials: R
authors.lastname: Shamri
authors.forename: Sara
authors.initials: S
authors.lastname: Feigelson
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D016022:Case-Control Studies; D002461:Cell Line, Transformed; D004355:Drug Stability; D004789:Enzyme Activation / Q000235:genetics; D004854:Herpesvirus 4, Human; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D016023:Integrins / Q000737:chemistry / Q000378:metabolism*; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D039041:Integrin alpha4beta1; D016023:Integrins; D019010:Vascular Cell Adhesion Molecule-1; D020827:rap1 GTP-Binding Proteins