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Blood, 1 February 2004, Vol. 103, No. 3, pp. 1033-1036.
Prepublished online as a Blood First Edition Paper on October 9, 2003; DOI 10.1182/blood-2003-07-2499.
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IMMUNOBIOLOGY
Brief report
LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds
Tatsuo Kinashi,
Memet Aker,
Maya Sokolovsky-Eisenberg,
Valentin Grabovsky,
Chisato Tanaka,
Revital Shamri,
Sara Feigelson,
Amos Etzioni, and
Ronen Alon
From the Bayer-chair Department of Molecular Immunology and Allergy, Graduate School of Medicine, Kyoto University, Kyoto, Japan; the Division of Pediatric Hemato-Oncology, Hadassah Medical Center, Jerusalem, Israel; the Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel; and the Department of Pediatrics, Meyer Children Hospital, Rambam Medical Center and the B. Rappaport School of Medicine, Technion, Haifa, Israel.
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." (Blood. 2004;103:1033-1036)
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