Journal of Clinical Immunology

, Volume 34, Issue 8, pp 900–903 | Cite as

Leukocyte Adhesion Deficiency III - When Integrins Activation Fails

  • Amos Etzioni
Key Review Article

Leukocyte adhesion deficiency (LAD) syndromes are a group of genetic conditions in which adhesion of leukocyte to the endothelium is defective in one of the various phases of the adhesion cascade [1]. The first described defect, LAD I, was described more than 30 years ago, is due to mutation in the gene encoded for the β2 subunit of the integrin which is essential for the firm adhesion of leukocytes to the blood vessel endothelium [2]. In LAD II the first phase of the adhesion cascade, the rolling phase is defective. In this condition the ligand for the selectin on the leukocyte is absence due to a defect in fucosylation [3].

Still, most of the attention in the field is focused today on the third syndrome, LAD III, through which many new aspects regarding leukocyte adhesion were discovered.

In 1997 Kuijpers et al. [4] described a Turkish child of a consanguineous parents who presented with a mild LAD I phenotype, mainly recurrent bacterial infections without apparent pus formation and...


Leukocyte Adhesion Deficiency III kindlin 3 immunodeficiency 


  1. 1.
    Schmidt S, Moser M, Sperandio M. The molecular basis of leukocyte recruitment and its deficiencies. Mol Immunol. 2013;55:49–58.PubMedCrossRefGoogle Scholar
  2. 2.
    Hanna S, Etzioni A. Leukocyte adhesion deficiencies. Ann N Y Acad Sci. 2012;1250:50–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Etzioni A, Frydman M, Pollack S, et al. Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med. 1992;327:1789–92.PubMedCrossRefGoogle Scholar
  4. 4.
    Kuijpers TW, Van Lier R, Hamann D, et al. Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins. J Clin Invest. 1997;100:1725–33.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    McDowall A, Inwald D, Leitinger B, et al. A novel form of integrin dysfunction involving beta1, beta2, and beta3 integrins. J Clin Invest. 2003;111(1):51–60.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Alon R, Aker M, Feigelson S, et al. A novel genetic leukocyte adhesion deficiency in subsecond triggering of integrin avidity by endothelial chemokines results in impaired leukocyte arrest on vascular endothelium under shear flow. Blood. 2003;101:4437–45.PubMedCrossRefGoogle Scholar
  7. 7.
    Harris ES, Shigeoka AO, Li W, Adams RH, Prescott SM, McIntyre TM, et al. A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins. Blood. 2001;97:767–76.PubMedCrossRefGoogle Scholar
  8. 8.
    Alon R, Etzioni A. LAD III a novel group of leukocyte integrin activation deficiencies. Trends Immunol. 2003;24:561–6.PubMedCrossRefGoogle Scholar
  9. 9.
    van de Vijver E, van den Berg TK, Kuijpers TW, et al. Leukocyte adhesion deficiencies. Hematol Oncol Clin N Am. 2013;27:101–16.CrossRefGoogle Scholar
  10. 10.
    Kuijpers TW, van Bruggen R, Kamerbeek N, et al. Natural history and early diagnosis of LAD-1/variant syndrome. Blood. 2007;109:3529–37.PubMedCrossRefGoogle Scholar
  11. 11.
    Moutsopoulos NM, Konkel J, Samadi M, et al. Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17 driven inflammatory bone loss. Sci Transl Med. 2014;6:229ra40v.CrossRefGoogle Scholar
  12. 12.
    Etzioni A. Genetic etiologies of leukocyte adhesion defects. Curr Opin Immunol. 2009;21:481–6.PubMedCrossRefGoogle Scholar
  13. 13.
    van de Vijver E, De Cuyper IM, Gerrits AJ, et al. Defects in Glanzmann thrombasthenia and LAD III (LAD-I/v) syndrome: the role of integrin β1 and β3 in platelet adhesion to collagen. Blood. 2012;119:583–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Kinashi T, Aker M, Sokolovsky-Eisenberg M, et al. LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood. 2004;103:1033–6.PubMedCrossRefGoogle Scholar
  15. 15.
    Pasvolsky R, Feigelson SW, Kilic S, et al. LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets. J Exp Med. 2007;204(7):1571–82.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Malinin NL, Zhang L, Choi J, et al. A point mutation in kindlin3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009;15:313–8.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Etzioni A, Alon R. Cell adhesion and leukocyte adhesion defects. In: Ochs HD, Smith EM, Puck J, editors. Primary immune deficiency disease. A molecular and genetic approach. 3rd ed. Oxford: Oxford University; 2014. p. 723–41.Google Scholar
  18. 18.
    Gruda R, Brown AC, Grabovsky V, et al. Loss of kindlin-3 alters the threshold for NK cell activation in human leukocyte adhesion deficiency-III. Blood. 2012;120(19):3915–24.PubMedCrossRefGoogle Scholar
  19. 19.
    Crittenden JR, Bergmeier W, Zhang Y, et al. CalDAG-GEFI integrates signaling for platelet aggregation and thrombus formation. Nat Med. 2004;10(9):982–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Harris ES, Smith TL, Springett GM, et al. Leukocyte adhesion deficiency I-variant syndrome(LAD-Iv, LADIII): molecular characterization of the defect in an index family. Am J Hematol. 2012;87:311–3.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Moser M, Nieswandt B, Ussar S, et al. Kidlin3 is essential for integrin activation and platelet aggregation. Nat Med. 2008;14:325–30.PubMedCrossRefGoogle Scholar
  22. 22.
    Fagerholm SC, Lek HS, Morrison VL. Kindlin -3 in the immune system. Am J Clin Exp Immunol. 2014;3:37–42.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Meves A, Stremmel C, Gottschalk K, Fässler R. The Kindlin protein family: new members to the club of focal adhesion proteins. Trends Cell Biol. 2009;19:504–13.PubMedCrossRefGoogle Scholar
  24. 24.
    Morrison VL, Macpherson M, Savinko T, et al. The beta2 integrin-kindlin-3 interaction is essential for T-cell homing but dispensable for T-cell activation in vivo. Blood. 2013;122:1428–36.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Lefort CT, Rossaint J, Moser M, et al. Distinct roles for talin-1 and kindlin-3 in LFA-1 extension and affinity regulation. Blood. 2012;119:4275–82.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Cohen SJ, Gurevich I, Feigelson SW, et al. The integrin coactivator Kindlin 3 is not required for lymphocyte diapedesis. Blood. 2013;122:2609–17.PubMedCrossRefGoogle Scholar
  27. 27.
    Schmidt S, Nakchbandi I, Ruppert R, et al. Kindlin-3-mediated signaling from multiple integrin classes is required for osteoclast-mediated bone resorption. J Cell Biol. 2011;192:883–97.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Kilic SS, Etzioni A. The clinical spectrum of leukocyte adhesion deficiency (LAD) III due to defective CalDAG-GEF1. J Clin Immunol. 2009;29(1):117–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Svensson L, Howarth K, McDowall A, et al. Leukocyte adhesion deficiency III is caused by mutations in kindling 3 affecting integrin activation. Nat Med. 2009;15:306–12.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Mory A, Feigelson SW, Yarali N, et al. Kindlin3 a new gene involved in the pathogenesis of LAD III. Blood. 2008;112:2591–2.PubMedCrossRefGoogle Scholar
  31. 31.
    Van de Vijver E, Maddalena A, Sanal O, et al. Hematologically important mutations: leukocyte adhesion deficiency (first update). Blood Cells Mol Dis. 2012;48:53–61.PubMedCrossRefGoogle Scholar
  32. 32.
    Kuijpers TW, van de Vijver E, Weterman MAJ, et al. LAD-I/variant syndrome is caused by mutations in FERMT3. Blood. 2009;113:4740–6.PubMedCrossRefGoogle Scholar
  33. 33.
    Canault M, Ghalloussi D, Grosdidier C, et al. Human CalDAG-GEFi gene (RASGRP2) mutation affects platelet function and causes severe bleeding. J Exp Med. 2014;211:1349–62.PubMedCrossRefGoogle Scholar
  34. 34.
    Elhasid R, Kilic SS, Ben-Harush M, et al. Prompt recovery of recipient hematopoiesis following two consecutive haploidentical peripheral blood stem cell transplantation in a child with leukocyte adhesion deficiency III (LADIII) syndrome. Bone Marrow Transplant. 2010;45:413–4.PubMedCrossRefGoogle Scholar
  35. 35.
    Robert P, Canault M, Farnarier C, et al. A novel leukocyte adhesion deficiency III variant: kindling 3 deficiency results in integrin and nonintegrin related defects in different steps of leukocyte adhesion. J Immunol. 2011;186:5273–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Mcdowall A, Svensson L, Stanley P, et al. Two mutations in the Kindlin3 gene of a new leukocyte adhesion deficiency III patient reveal distinct effects on leukocyte function in vitro. Blood. 2010;115:4834–42.PubMedCrossRefGoogle Scholar
  37. 37.
    Jurk K, Schulz AS, Kehrel BE, et al. Novel integrin dependent platelet malfunction in siblings with leukocyte adhesion deficiency III (LAD-III) caused by a point mutation in FERMT3. Thromb Haemost. 2010;103:1053–64.PubMedCrossRefGoogle Scholar
  38. 38.
    Meller J, Malinin NL, Panigrahi S, et al. Novel aspects of Kindlin 3 function in humans basic on a new case of leukocyte adhesion deficiency III. J Thromb Haematol. 2012;10:1397–408.Google Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Ruth Children Hospital, HaifaRappaport Medical SchoolTechnionIsrael
  2. 2.Ruth Children HospitalRambam Medical CampusHaifaIsrael

Personalised recommendations