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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.

SUBMITTER: Pasvolsky R

PROVIDER: S-EPMC2118641 | biostudies-literature | 2007 Jul

REPOSITORIES: biostudies-literature

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

Pasvolsky Ronit R Feigelson Sara W SW Kilic Sara Sebnem SS Simon Amos J AJ Tal-Lapidot Guy G Grabovsky Valentin V Crittenden Jill R JR Amariglio Ninette N Safran Michal M Graybiel Ann M AM Rechavi Gideon G Ben-Dor Shifra S Etzioni Amos A Alon Ronen R

The Journal of experimental medicine 20070618 7

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-GE ...[more]

PMID: 17576779

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Project description:BackgroundNeutrophils to lymphocytes ratio (NLR) and platelets to lymphocytes ratio (PLR) are both inflammatory ratios that can be easily calculated from a simple blood count. They are frequently reported and tested as prognostic factors in several medical disciplines. Pregnancy involves special reference values for laboratory assays.ObjectiveThe aim of this study was to define pregnancy-related reference values for NLR and PLR according to trimester, background morbidity and according to the patient's age.Study designA retrospective analysis of a large cohort undergoing community-based pregnancy surveillance between the years 2011-2016. Data were analyzed according to high-risk patient versus normal-risk patient.ResultsA total of 11,415 patients were included. Mean PLR and NLR values were 136.3±44.3, 2.6±1, respectively during the first trimester, 144.6±47.1, 4.0±1.4 respectively during the second trimester and 118.1±42.0, 3.5±1.2 respectively during the third trimester. No difference was detected between the high-risk and the normal population (P-values 0.3, 0.5 and 0.4 for PLR in each trimester respectively and 0.3, 0.4, 0.6 for NLR in each trimester, respectively). No differences were detected among parity categories. The correlation between patient's age and either PLR and NLR was a weak positive correlation (though statistically significant). Both PLR and NLR reached a maximum value during the second trimester. The differences between mean NLR and PLR between trimesters were significant (P <0.01 for all differences tested). PLR rises in the presence of anemia, reaching statistical significance (P-value for PLR in each trimester was <0.01). NLR showed an opposite trend (P-values for NLR were 0.4, 0.005 and 0.06 in each trimester, respectively).ConclusionsIn our cohort, there were generally no differences between the high-risk and the normal population, excluding patients with a fibroid uterus or inflammatory bowel disease who presented a significantly elevated PLR through all trimesters. Both PLR and NLR reached a maximum value during the second trimester and were positively correlated with age. We anticipate that the population-based data will assist in providing accurate reference values for future research testing NLR and PLR measures during pregnancy.

Dataset Information

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

Publications

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

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