title: A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow.
abstract: Leukocyte arrest on vascular endothelium under disruptive shear flow is a multistep process that requires in situ integrin activation on the leukocyte surface by endothelium-displayed chemoattractants, primarily chemokines. A genetic deficiency of leukocyte adhesion to endothelium associated with defective beta2 integrin expression or function (LAD-1) has been described. We now report a novel severe genetic disorder in this multistep process associated with functional defects in multiple leukocyte integrins, reflected in recurrent infections, profound leukocytosis, and a bleeding tendency. This syndrome is associated with an impaired ability of neutrophil and lymphocyte beta1 and beta2 integrins to generate high avidity to their endothelial ligands and arrest cells on vascular endothelium in response to endothelial chemoattractant signals. Patient leukocytes roll normally on endothelial selectins, express intact integrins and G protein-coupled chemokine receptors (GPCR), spread on integrin ligands, and migrate normally along a chemotactic gradient. Activation of beta2 integrins in response to GPCR signals and intrinsic soluble ligand binding properties of the very late activation antigen-4 (VLA-4) integrin are also retained in patient leukocytes. Nevertheless, all integrins fail to generate firm adhesion to immobilized ligands in response to in situ GPCR-mediated activation by chemokines or chemoattractants, a result of a primary defect in integrin rearrangement at ligand-bearing contacts. This syndrome is the first example of a human integrin-activation deficiency associated with defective GPCR stimulation of integrin avidity at subsecond contacts, a key step in leukocyte arrest on vascular endothelium under shear flow.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science Rehovot, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Sara
authors.initials: S
authors.lastname: Feigelson
authors.forename: Maya
authors.initials: M
authors.lastname: Sokolovsky-Eisenberg
authors.forename: Donald E
authors.initials: DE
authors.lastname: Staunton
authors.forename: Guy
authors.initials: G
authors.lastname: Cinamon
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Revital
authors.initials: R
authors.lastname: Shamri
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
mesh_terms: D002448:Cell Adhesion; D018925:Chemokines / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D002648:Child; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology* / Q000502:physiology; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D036904:Leukocyte Rolling; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000097:blood / Q000209:etiology / Q000473:pathology*; D007962:Leukocytes / Q000737:chemistry / Q000473:pathology; D008297:Male; D010477:Perfusion; D019707:Receptors, Chemokine / Q000378:metabolism; D013314:Stress, Mechanical; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D018925:Chemokines; D016023:Integrins; D019707:Receptors, Chemokine