SEARCH:   Advanced

Prepublished online as a Blood First Edition Paper on February 20, 2003; DOI 10.1182/blood-2002-11-3427. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-11-3427v1 101/11/4437    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Alon, R. Articles by Etzioni, A. Search for Related Content PubMed PubMed Citation Articles by Alon, R. Articles by Etzioni, A. Related Collections Hemostasis, Thrombosis, and Vascular Biology Phagocytes Cell Adhesion and Motility Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 June 2003, Vol. 101, No. 11, pp. 4437-4445 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY 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 From the Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; Division of Pediatric Hemato-Oncology, Hadassah Medical Center, Jerusalem, Israel; ICOS, Bothell, WA; and Department of Pediatrics, Meyer Children Hospital, Rambam Medical Center, and the B. Rappaport School of Medicine, Technion, Haifa, Israel. 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 2 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 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 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: T. Kuijpers, F. Baas, M. Weterman, A. Tool, and D. Roos Response: Adherence to the LAD variant form Blood, December 1, 2007; 110(12): 4129 - 4130. [Full Text] [PDF] R. Pasvolsky, S. W. Feigelson, S. S. Kilic, A. J. Simon, G. Tal-Lapidot, V. Grabovsky, J. R. Crittenden, N. Amariglio, M. Safran, A. M. Graybiel, et al. A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets J. Exp. Med., July 9, 2007; 204(7): 1571 - 1582. [Abstract] [Full Text] [PDF] T. W. Kuijpers, R. v. Bruggen, N. Kamerbeek, A. T. J. Tool, G. Hicsonmez, A. Gurgey, A. Karow, A. J. Verhoeven, K. Seeger, O. Sanal, et al. Natural history and early diagnosis of LAD-1/variant syndrome Blood, April 15, 2007; 109(8): 3529 - 3537. [Abstract] [Full Text] [PDF] T. Garrood, L. Lee, and C. Pitzalis Molecular mechanisms of cell recruitment to inflammatory sites: general and tissue-specific pathways Rheumatology, March 1, 2006; 45(3): 250 - 260. [Full Text] [PDF] S. A. Francis, X. Shen, J. B. Young, P. Kaul, and D. J. Lerner Rho GEF Lsc is required for normal polarization, migration, and adhesion of formyl-peptide-stimulated neutrophils Blood, February 15, 2006; 107(4): 1627 - 1635. [Abstract] [Full Text] [PDF] K. Yonekawa and J. M. Harlan Targeting leukocyte integrins in human diseases J. Leukoc. Biol., February 1, 2005; 77(2): 129 - 140. [Abstract] [Full Text] [PDF] G. J. Zwartz, A. Chigaev, D. C. Dwyer, T. D. Foutz, B. S. Edwards, and L. A. Sklar Real-time Analysis of Very Late Antigen-4 Affinity Modulation by Shear J. Biol. Chem., September 10, 2004; 279(37): 38277 - 38286. [Abstract] [Full Text] [PDF] T. Kinashi, M. Aker, M. Sokolovsky-Eisenberg, V. Grabovsky, C. Tanaka, R. Shamri, S. Feigelson, A. Etzioni, and R. Alon LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds Blood, February 1, 2004; 103(3): 1033 - 1036. [Abstract] [Full Text] [PDF] N. Hogg, M. Laschinger, K. Giles, and A. McDowall T-cell integrins: more than just sticking points J. Cell Sci., December 1, 2003; 116(23): 4695 - 4705. [Abstract] [Full Text] [PDF]

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020