The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20070058
The Journal of Experimental Medicine, Vol. 204, No. 7, 1571-1582
The Rockefeller University Press, 0022-1007 $30.00
© Pasvolsky et al.
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ARTICLE

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

Ronit Pasvolsky1, Sara W. Feigelson1, Sara Sebnem Kilic3, Amos J. Simon4, Guy Tal-Lapidot1, Valentin Grabovsky1, Jill R. Crittenden5, Ninette Amariglio4, Michal Safran4, Ann M. Graybiel5, Gideon Rechavi4, Shifra Ben-Dor2, Amos Etzioni6,7, and Ronen Alon1

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 {alpha}IIbß3 activation by key agonists. ß2 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 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.

Abbreviations used: GEF, guanine exchange factor; GPCR, G protein–coupled receptor; HUVEC, human umbilical vein endothelial cell; LAD, leukocyte adhesion deficiency; NMD, nonsense-mediated decay; PAF, platelet-activating factor; PLC, phospholipase C; SNP, single-nucleotide polymorphism.

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


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