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¹ Department of Immunology and ² Department of Biological Services, the Weizmann Institute of Science, Rehovot 76100, Israel
³ Department of Pediatric Immunology, Uludag University School of Medicine, Bursa 16059, Turkey
⁴ Pediatric Hematology-Oncology, Safra Children's Hospital, The Chaim Sheba Medical Center, Tel-Hashomer 52621, Israel
⁵ Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139
⁶ Department of Pediatrics, Meyer Children's Hospital, Rambam Medical Center, Haifa 31096, Israel
⁷ B. Rappaport School of Medicine, Technion, Haifa 31096, Israel

CORRESPONDENCE Ronen Alon: ronen.alon{at}weizmann.ac.il OR Amos Etzioni: etzioni{at}rambam.health.gov.il

Leukocyte and platelet integrins rapidly alter their affinity and adhesiveness in response to various activation (inside-out) signals. A rare leukocyte adhesion deficiency (LAD), LAD-III, is associated with severe defects in leukocyte and platelet integrin activation. We report two new LAD cases in which lymphocytes, neutrophils, and platelets share severe defects in ß₁, ß₂, and ß₃ integrin activation. Patients were both homozygous for a splice junction mutation in their CalDAG-GEFI gene, which is a key Rap-1/2 guanine exchange factor (GEF). Both mRNA and protein levels of the GEF were diminished in LAD lymphocytes, neutrophils, and platelets. Consequently, LAD-III platelets failed to aggregate because of an impaired _IIbß₃ activation by key agonists. ß₂ integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNF-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil ß₂ integrin adhesiveness by surface-bound chemoattractants and of primary T lymphocyte LFA-1 by the CXCL12 chemokine was abolished. Chemokine inside-out signals also failed to stimulate lymphocyte LFA-1 extension and high affinity epitopes. Chemokine-triggered VLA-4 adhesiveness in T lymphocytes was partially defective as well. These studies identify CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets.

R. Pasvolsky, S.W. Feigelson, and S.S. Kilic contributed equally to this paper.

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