title: A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets.
abstract: 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 beta(1), beta(2), and beta(3) 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 alpha(IIb)beta(3) activation by key agonists. beta(2) integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNFalpha-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 CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets.
authors.affiliation: Department of Immunology, the Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Pasvolsky
authors.forename: Sara W
authors.initials: SW
authors.lastname: Feigelson
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Guy
authors.initials: G
authors.lastname: Tal-Lapidot
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Jill R
authors.initials: JR
authors.lastname: Crittenden
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Michal
authors.initials: M
authors.lastname: Safran
authors.forename: Ann M
authors.initials: AM
authors.lastname: Graybiel
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Shifra
authors.initials: S
authors.lastname: Ben-Dor
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D001483:Base Sequence; D001792:Blood Platelets / Q000502:physiology*; D002449:Cell Aggregation; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D016023:Integrins / Q000097:blood; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics*; D008214:Lymphocytes / Q000502:physiology*; D009154:Mutation; D009504:Neutrophils / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; C415483:RASGRP2 protein, human