A Novel Leukocyte Adhesion Deficiency III Variant: Kindlin-3 Deficiency Results in Integrin and Nonintegrin-Related Defects in Different Steps of Leukocyte Adhesion
Philippe Robert,Matthias Canault,Catherine Farnarier,Alan T. Nurden,Charlotte Grosdidier,Vincent Barlogis,Pierre Bongrand,Anne Pierres,Anne Pierres,Hervé Chambost,Marie-Christine Alessi +10 more
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The results suggest looking for a possible kindlin-3 involvement in membrane dynamical event independent of integrin-mediated adhesion in a patient with a new mutation of FERMT3 and lack of kindlins-3 expression in platelets and leukocytes.Abstract:
Leukocyte adhesion deficiency type III is a recently described condition involving a Glanzmann-type bleeding syndrome and leukocyte adhesion deficiency. This was ascribed to a defect of the FERMT3 gene resulting in abnormal expression of kindlin-3, a protein expressed in hematopoietic cells with a major role in the regulation of integrin activation. In this article, we describe a patient with a new mutation of FERMT3 and lack of kindlin-3 expression in platelets and leukocytes. We assayed quantitatively the first steps of kindlin-3–defective leukocyte adhesion, namely, initial bond formation, bond strengthening, and early spreading. Initial bond formation was readily stimulated with neutrophils stimulated by fMLF, and neutrophils and lymphocytes stimulated by a phorbol ester or Mn 2+ . In contrast, attachment strengthening was defective in the patient’s lymphocytes treated with PMA or Mn 2+ , or fMLF-stimulated neutrophils. However, attachment strengthening was normal in patient’s neutrophils treated with phorbol ester or Mn 2+ . In addition, the patient’s T lymphocytes displayed defective integrin-mediated spreading and a moderate but significant decrease of spreading on anti-CD3–coated surfaces. Patient’s neutrophils displayed a drastic alteration of integrin-mediated spreading after fMLF or PMA stimulation, whereas signaling-independent Mn 2+ allowed significant spreading. In conclusion, the consequences of kindlin-3 deficiency on β 2 integrin function depend on both cell type and the stimulus used for integrin activation. Our results suggest looking for a possible kindlin-3 involvement in membrane dynamical event independent of integrin-mediated adhesion.read more
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Hematologically important mutations: leukocyte adhesion deficiency (first update).
Edith van de Vijver,Anne Maddalena,Ozden Sanal,Steven M. Holland,Gulbu Uzel,Manisha Madkaikar,Martin de Boer,Karin van Leeuwen,M. Yavuz Köker,Nima Parvaneh,Alain Fischer,S.K. Alex Law,Nigel Klein,F. Ilhan Tezcan,Ekrem Unal,Turkan Patiroglu,Bernd H. Belohradsky,Klaus Schwartz,Raz Somech,Taco W. Kuijpers,Dirk Roos +20 more
TL;DR: Leukocyte adhesion deficiency (LAD) is an immunodeficiency caused by defects in the adhesion of leukocytes (especially neutrophils) to the blood vessel wall, resulting in severe bacterial infections and impaired wound healing, accompanied by neutrophilia.
Journal ArticleDOI
Leukocyte Adhesion Deficiencies
TL;DR: Leukocyte adhesion deficiencies are caused by defects in the adhesion of leukocytes to the vessel wall, resulting in severe recurrent nonpussing infections and neutrophilia, often preceded by delayed separation of the umbilical cord.
Journal ArticleDOI
β2 Integrins As Regulators of Dendritic Cell, Monocyte, and Macrophage Function
TL;DR: How imbalances in β2 integrin function can have far-reaching effects on mounting appropriate immune responses, potentially influencing the development and progression of autoimmune and inflammatory diseases is discussed.
Journal ArticleDOI
Neutrophil arrest by LFA-1 activation.
Craig T. Lefort,Klaus Ley +1 more
TL;DR: Two FERM domain-containing proteins, talin-1 and Kindlin-3, are critical integrin co-activators and have distinct roles in the induction of LFA-1 conformational rearrangements.
Journal ArticleDOI
Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding
Matthias Canault,Matthias Canault,Matthias Canault,Dorsaf Ghalloussi,Dorsaf Ghalloussi,Dorsaf Ghalloussi,Charlotte Grosdidier,Charlotte Grosdidier,Charlotte Grosdidier,Marie Guinier,Claire Perret,Claire Perret,Claire Perret,Nadjim Chelghoum,Marine Germain,Marine Germain,Marine Germain,Hana Raslova,Franck Peiretti,Franck Peiretti,Franck Peiretti,Pierre Morange,Pierre Morange,Pierre Morange,Noémie Saut,Noémie Saut,Noémie Saut,Xavier Pillois,Alan T. Nurden,François Cambien,François Cambien,François Cambien,Anne Pierres,Anne Pierres,Anne Pierres,Timo K. van den Berg,Taco W. Kuijpers,Marie-Christine Alessi,Marie-Christine Alessi,Marie-Christine Alessi,David-Alexandre Trégouët,David-Alexandre Trégouët,David-Alexandre Trégouët +42 more
TL;DR: First case of a human RASGRP2 mutation affecting Rap1 activation in platelets and causing severe bleeding is reported.
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