Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Leukocyte-adhesion deficiency

Amos Etzioni, MD
Section Editor
Luigi D Notarangelo, MD
Deputy Editor
Anna M Feldweg, MD


Leukocyte trafficking from the bloodstream to tissue is important for the continuous surveillance of foreign antigens, as well as for rapid leukocyte accumulation at sites of inflammatory response or tissue injury. Leukocyte emigration to sites of inflammation is a dynamic process, involving multiple steps in an adhesion cascade. Various adhesion molecules are expressed on both resting and stimulated endothelial cells and leukocytes.

Defects in a number of these adhesion molecules result in recognized clinical syndromes. Three leukocyte-adhesion deficiency (LAD) syndromes have been delineated, and a fourth category of other neutrophil adhesion defects has been proposed [1]:

LAD I, in which the beta-2 integrin family is deficient or defective.

LAD II, in which the fucosylated carbohydrate ligands for selectins are absent.

LAD III, in which activation of all beta integrins (1, 2, and 3) is defective.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Mar 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Etzioni A. Genetic etiologies of leukocyte adhesion defects. Curr Opin Immunol 2009; 21:481.
  2. Picard C, Al-Herz W, Bousfiha A, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol 2015; 35:696.
  3. Etzioni A, Alon R. Cell adhesion and leukocyte adhesion defects. In: Primary Immunodeficiency Diseases: A Molecular and Genetic Approach, 3rd ed, Ochs HD, Smith CIE, Puck JM (Eds), Oxford University Press, New York 2014. p.723.
  4. Harlan JM, Killen PD, Senecal FM, et al. The role of neutrophil membrane glycoprotein GP-150 in neutrophil adherence to endothelium in vitro. Blood 1985; 66:167.
  5. Castriconi R, Dondero A, Cantoni C, et al. Functional characterization of natural killer cells in type I leukocyte adhesion deficiency. Blood 2007; 109:4873.
  6. Roos D, Law SK. Hematologically important mutations: leukocyte adhesion deficiency. Blood Cells Mol Dis 2001; 27:1000.
  7. Mathew EC, Shaw JM, Bonilla FA, et al. A novel point mutation in CD18 causing the expression of dysfunctional CD11/CD18 leucocyte integrins in a patient with leucocyte adhesion deficiency (LAD). Clin Exp Immunol 2000; 121:133.
  8. Solomon E, Palmer RW, Hing S, Law SK. Regional localization of CD18, the beta-subunit of the cell surface adhesion molecule LFA-1, on human chromosome 21 by in situ hybridization. Ann Hum Genet 1988; 52:123.
  9. Vihinen M, Arredondo-Vega FX, Casanova JL, et al. Primary immunodeficiency mutation databases. Adv Genet 2001; 43:103.
  10. Hogg N, Stewart MP, Scarth SL, et al. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest 1999; 103:97.
  11. Uzel G, Tng E, Rosenzweig SD, et al. Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). Blood 2008; 111:209.
  12. Stark MA, Huo Y, Burcin TL, et al. Phagocytosis of apoptotic neutrophils regulates granulopoiesis via IL-23 and IL-17. Immunity 2005; 22:285.
  13. Smith E, Zarbock A, Stark MA, et al. IL-23 is required for neutrophil homeostasis in normal and neutrophilic mice. J Immunol 2007; 179:8274.
  14. Moutsopoulos NM, Konkel J, Sarmadi 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; 6:229ra40.
  15. Fischer A, Lisowska-Grospierre B, Anderson DC, Springer TA. Leukocyte adhesion deficiency: molecular basis and functional consequences. Immunodefic Rev 1988; 1:39.
  16. Movahedi M, Entezari N, Pourpak Z, et al. Clinical and laboratory findings in Iranian patients with leukocyte adhesion deficiency (study of 15 cases). J Clin Immunol 2007; 27:302.
  17. Rosenzweig SD, Uzel G, Holland SM. Phagocyte disorders. In: Immunologic disorders in infants and children, Stiehm ER, Ochs HD, Winkelstein JA (Eds), Elsevier Saunders, Philadelphia 2004. p.632.
  18. Ganesh A, Al-Zuhaibi SS, Bialasiewicz AA, et al. Necrotizing Pseudomonas infection of the ocular adnexa in an infant with leukocyte adhesion defect. J Pediatr Ophthalmol Strabismus 2007; 44:199.
  19. Anderson DC, Mace ML, Brinkley BR, et al. Recurrent infection in glycogenosis type Ib: abnormal neutrophil motility related to impaired redistribution of adhesion sites. J Infect Dis 1981; 143:447.
  20. Dababneh R, Al-Wahadneh AM, Hamadneh S, et al. Periodontal manifestation of leukocyte adhesion deficiency type I. J Periodontol 2008; 79:764.
  21. Cox DP, Weathers DR. Leukocyte adhesion deficiency type 1: an important consideration in the clinical differential diagnosis of prepubertal periodontitis. A case report and review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105:86.
  22. Hanna S, Etzioni A. Leukocyte adhesion deficiencies. Ann N Y Acad Sci 2012; 1250:50.
  23. Hajishengallis G, Moutsopoulos NM. Role of bacteria in leukocyte adhesion deficiency-associated periodontitis. Microb Pathog 2016; 94:21.
  24. Moutsopoulos NM, Chalmers NI, Barb JJ, et al. Subgingival microbial communities in Leukocyte Adhesion Deficiency and their relationship with local immunopathology. PLoS Pathog 2015; 11:e1004698.
  25. Levy-Mendelovich S, Rechavi E, Abuzaitoun O, et al. Highlighting the problematic reliance on CD18 for diagnosing leukocyte adhesion deficiency type 1. Immunol Res 2016; 64:476.
  26. Weening RS, Bredius RG, Wolf H, van der Schoot CE. Prenatal diagnostic procedure for leukocyte adhesion deficiency. Prenat Diagn 1991; 11:193.
  27. Lorusso F, Kong D, Jalil AK, et al. Preimplantation genetic diagnosis of leukocyte adhesion deficiency type I. Fertil Steril 2006; 85:494.e15.
  28. Moutsopoulos NM, Zerbe CS, Wild T, et al. Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1. N Engl J Med 2017; 376:1141.
  29. Qasim W, Cavazzana-Calvo M, Davies EG, et al. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency. Pediatrics 2009; 123:836.
  30. Bauer TR Jr, Hai M, Tuschong LM, et al. Correction of the disease phenotype in canine leukocyte adhesion deficiency using ex vivo hematopoietic stem cell gene therapy. Blood 2006; 108:3313.
  31. Bauer TR Jr, Allen JM, Hai M, et al. Successful treatment of canine leukocyte adhesion deficiency by foamy virus vectors. Nat Med 2008; 14:93.
  32. Bauer TR Jr, Hickstein DD. Gene therapy for leukocyte adhesion deficiency. Curr Opin Mol Ther 2000; 2:383.
  33. Al-Ghonaium A. Stem cell transplantation for primary immunodeficiencies: King Faisal Specialist Hospital experience from 1993 to 2006. Bone Marrow Transplant 2008; 42 Suppl 1:S53.
  34. Gennery AR, Cant AJ. Advances in hematopoietic stem cell transplantation for primary immunodeficiency. Immunol Allergy Clin North Am 2008; 28:439.
  35. 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.
  36. Becker DJ, Lowe JB. Fucose: biosynthesis and biological function in mammals. Glycobiology 2003; 13:41R.
  37. Lübke T, Marquardt T, Etzioni A, et al. Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat Genet 2001; 28:73.
  38. Gazit Y, Mory A, Etzioni A, et al. Leukocyte adhesion deficiency type II: long-term follow-up and review of the literature. J Clin Immunol 2010; 30:308.
  39. Helmus Y, Denecke J, Yakubenia S, et al. Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter. Blood 2006; 107:3959.
  40. Phillips ML, Schwartz BR, Etzioni A, et al. Neutrophil adhesion in leukocyte adhesion deficiency syndrome type 2. J Clin Invest 1995; 96:2898.
  41. von Andrian UH, Berger EM, Ramezani L, et al. In vivo behavior of neutrophils from two patients with distinct inherited leukocyte adhesion deficiency syndromes. J Clin Invest 1993; 91:2893.
  42. Kuijpers TW, Etzioni A, Pollack S, Pals ST. Antigen-specific immune responsiveness and lymphocyte recruitment in leukocyte adhesion deficiency type II. Int Immunol 1997; 9:607.
  43. Austrup F, Vestweber D, Borges E, et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflammed tissues. Nature 1997; 385:81.
  44. Borges E, Tietz W, Steegmaier M, et al. P-selectin glycoprotein ligand-1 (PSGL-1) on T helper 1 but not on T helper 2 cells binds to P-selectin and supports migration into inflamed skin. J Exp Med 1997; 185:573.
  45. Wild MK, Lühn K, Marquardt T, Vestweber D. Leukocyte adhesion deficiency II: therapy and genetic defect. Cells Tissues Organs 2002; 172:161.
  46. Hidalgo A, Ma S, Peired AJ, et al. Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. Blood 2003; 101:1705.
  47. Yakubenia S, Wild MK. Leukocyte adhesion deficiency II. Advances and open questions. FEBS J 2006; 273:4390.
  48. Etzioni A, Gershoni-Baruch R, Pollack S, Shehadeh N. Leukocyte adhesion deficiency type II: long-term follow-up. J Allergy Clin Immunol 1998; 102:323.
  49. Dauber A, Ercan A, Lee J, et al. Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect. Hum Mol Genet 2014; 23:2880.
  50. Marquardt T, Lühn K, Srikrishna G, et al. Correction of leukocyte adhesion deficiency type II with oral fucose. Blood 1999; 94:3976.
  51. Svensson L, Howarth K, McDowall A, et al. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med 2009; 15:306.
  52. McDowall A, Inwald D, Leitinger B, et al. A novel form of integrin dysfunction involving beta1, beta2, and beta3 integrins. J Clin Invest 2003; 111:51.
  53. Kuijpers TW, van Bruggen R, Kamerbeek N, et al. Natural history and early diagnosis of LAD-1/variant syndrome. Blood 2007; 109:3529.
  54. 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.
  55. Mory A, Feigelson SW, Yarali N, et al. Kindlin-3: a new gene involved in the pathogenesis of LAD-III. Blood 2008; 112:2591.
  56. 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.
  57. 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.
  58. Bergmeier W, Goerge T, Wang HW, et al. Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III. J Clin Invest 2007; 117:1699.
  59. Hidalgo A, Frenette PS. When integrins fail to integrate. Nat Med 2009; 15:249.
  60. van de Vijver E, Tool AT, Sanal Ö, et al. Kindlin-3-independent adhesion of neutrophils from patients with leukocyte adhesion deficiency type III. J Allergy Clin Immunol 2014; 133:1215.
  61. Kuijpers TW, van de Vijver E, Weterman MA, et al. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood 2009; 113:4740.
  62. 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.
  63. Alon R, Etzioni A. LAD-III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol 2003; 24:561.
  64. 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; 120:3915.
  65. 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.
  66. Stepensky PY, Wolach B, Gavrieli R, et al. Leukocyte adhesion deficiency type III: clinical features and treatment with stem cell transplantation. J Pediatr Hematol Oncol 2015; 37:264.
  67. DeLisser HM, Christofidou-Solomidou M, Sun J, et al. Loss of endothelial surface expression of E-selectin in a patient with recurrent infections. Blood 1999; 94:884.
  68. Dharmawardhane S, Bokoch GM. Rho GTPases and leukocyte cytoskeletal regulation. Curr Opin Hematol 1997; 4:12.
  69. Knaus UG, Heyworth PG, Evans T, et al. Regulation of phagocyte oxygen radical production by the GTP-binding protein Rac 2. Science 1991; 254:1512.
  70. Roberts AW, Kim C, Zhen L, et al. Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 1999; 10:183.
  71. Ambruso DR, Knall C, Abell AN, et al. Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 2000; 97:4654.
  72. Williams DA, Tao W, Yang F, et al. Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 2000; 96:1646.
  73. Kurkchubasche AG, Panepinto JA, Tracy TF Jr, et al. Clinical features of a human Rac2 mutation: a complex neutrophil dysfunction disease. J Pediatr 2001; 139:141.
  74. Roos D, Kuijpers TW, Mascart-Lemone F, et al. A novel syndrome of severe neutrophil dysfunction: unresponsiveness confined to chemotaxin-induced functions. Blood 1993; 81:2735.
  75. Accetta D, Syverson G, Bonacci B, et al. Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J Allergy Clin Immunol 2011; 127:535.
  76. Alkhairy OK, Rezaei N, Graham RR, et al. RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. J Allergy Clin Immunol 2015; 135:1380.
  77. Simpson BN, Hogg N, Svensson LM, et al. A new leukocyte hyperadhesion syndrome of delayed cord separation, skin infection, and nephrosis. Pediatrics 2014; 133:e257.