Pasvolsky, RonitFeigelson, Sara W.Kılıç, Sara ŞebnemSimon, Amos J.Tal-Lapidot, GuyGrabovsky, ValentinCrittenden, Jill R.Amariglio, NinetteSafran, MichalGraybiel, Ann M.Rechavi, GideonBen-Dor, ShifraEtzioni, AmosAlon, Ronen2024-11-072024-11-072007-07-090022-1007https://doi.org/10.1084/jem.20070058https://rupress.org/jem/article-abstract/204/7/1571/46834/A-LAD-III-syndrome-is-associated-with-defective?redirectedFrom=fulltexthttps://hdl.handle.net/11452/47586Leukocyte 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 beta(1), beta(2), and beta(3) integrin activation. Patients were both homozygous for a splice junction mutation in their CaIDAG-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-II platelets failed to aggregate because of an impaired alpha(IIb)beta(3) activation by key agonists. beta(2) integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNF alpha-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil beta(2) 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 CaIDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets.eninfo:eu-repo/semantics/openAccessLeukocyte adhesion deficiencySmall gtpase rap1Integrin mac-1 cd11b/cd18T-cellVascular endotheliumAffinity modulationExchange factorArrestChemokinesSignalsImmunologyResearch & experimental medicineArticle00024799800001015711582204710.1084/jem.20070058