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Prepublished online as a Blood First Edition Paper on February 20, 2003; DOI 10.1182/blood-2002-11-3427.
Submitted November 12, 2002
Accepted January 30, 2003
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
Ronen Alon, Memet Aker, Sara Feigelson, Maya Sokolovsky-Eisenberg, Donald E Staunton, Guy Cinamon, Valentin Grabovsky, Revital Shamri, and Amos Etzioni*
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Division of Pediatric Hemato-Oncology, Hadassah Medical Center, Jerusalem, Israel
ICOS Corp., Bothell, WA, USA
Department of Pediatrics, Rambam Medical Center, Technion, Haifa, Israel
* Corresponding author; email: etzioni{at}rambam.health.gov.il.
Leukocyte arrest on vascular endothelium under disruptive shear flow is a multi-step process which 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 b2 integrin expression or function (LAD-I) has been described. We now report a novel severe genetic disorder in this multi-step process associated with functional defects in multiple leukocyte integrins, reflected in recurrent infections, profound leukocytosis and a bleeding tendency. This syndrome is associated in an impaired ability of neutrophil and lymphocyte  1 and 2 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 2 integrins in response to GPCR signals and intrinsic soluble ligand binding properties of the 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.
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