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 affi nity and adhesiveness in response to various activation (inside-out) signals. A rare leukocyte adhesion defi ciency (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 β 1 , β 2 , and β 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 α IIb β 3 activation by key agonists.β 2 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 β 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 affi nity 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.