A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets

Ronit Pasvolsky, Sara W. Feigelson, Sara Sebnem Kilic, Amos J. Simon, Guy Tal-Lapidot, Valentin Grabovsky, Jill R. Crittenden, Ninette Amariglio, Michal Safran, Ann M. Graybiel, Gideon Rechavi, Shifra Ben-Dor, Amos Etzioni*, Ronen Alon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

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 β1, β2, and β3 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 αIIbβ3 activation by key agonists. β2 integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNFα-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil β2 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. JEM

Original languageEnglish
Pages (from-to)1571-1582
Number of pages12
JournalJournal of Experimental Medicine
Volume204
Issue number7
DOIs
StatePublished - 9 Jul 2007
Externally publishedYes

Funding

FundersFunder number
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentR37HD028341

    Fingerprint

    Dive into the research topics of 'A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets'. Together they form a unique fingerprint.

    Cite this