Abstract
Leukocyte trafficking from bloodstream to tissue is important for the continuous surveillance for foreign antigens as well as for rapid leukocyte accumulation at sites of inflammatory response or tissue injury. Leukocyte interaction with vascular endothelial cells is a pivotal event in the inflammatory response and is mediated by several families of adhesion molecules. The crucial role of the β2-integrin subfamily in leukocyte emigration was established after leukocyte adhesion deficiency (LAD) I was discovered. Patients with this disorder suffer from life-threatening bacterial infections, and in its severe form, death usually occurs in early childhood unless bone marrow transplantation is performed. The LAD II disorder clarifies the role of the selectin receptors and their fucosylated ligands. Clinically, patients with LAD II suffer not only from a less severe form of infectious episodes resembling the moderate phenotype of LAD I but also from severe psychomotor and growth retardation. LAD III emphasizes the importance of the integrin-activation phase in the adhesion cascade. All hematopoietic integrin activation processes are defective, which lead to severe infection as observed in LAD I and to marked increase tendency for bleeding problems (defective activation of β1, β2, and β3 integrins). The various genetic defects leading to all adhesion molecules syndrome will be discussed.
Similar content being viewed by others
References
Carlos TM, Harlan JM (1994) Leukocyte-endothelial adhesion molecules. Blood 84(7):2068–2101
Luster AD, Alon R, von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6(12):1182–1190
Abram CL, Lowell CA (2009) The ins and outs of leukocyte integrin signaling. Ann Rev Immunol 27:339–362
Shamri R, Grabovsky V, Gauguet JM, Feigelson S, Manevich E, Kolanus W, Robinson MK, Staunton DE, von Andrian UH, Alon R (2005) Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat Immunol 6(5):497–506
Pasvolsky R, Feigelson SW, Kilic SS et al (2007) A LADIII syndrome is associated with effective expression of the Rap-1 activator alDAG-GEF1 in lymphocyte, neutrophils and platelets. J Exp Med 204(7):1571–1582
Anderson DC, Smith CW (2001) Leukocyte adhesion deficiency and other disorders of leukocyte adherence and motility. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited diseases, 7th edn. McGraw-Hill, New York, pp 3955–3995
Etzioni A (1996) Adhesion molecules-their role in health and disease. Pediatr Res 39(2):191–198
Fischer A, Lisowska-Grospierre B, Anderson DC, Springer T (1988) Leukocyte adhesion deficiency: molecular basis and functional consequences. Immunol Rev 1(1):39–54
von Adrian UH, Berger EM, Ramezani L, Chambers JD et al (1993) In vivo behavior of neutrophils from two patients with distinct inherited leukocyte adhesion deficiency syndromes. J Clin Invest 91(6):2893–2897
Hogg N, Stewart MP, Scarth SL, Newton R, Shaw JM, Law SK, Klein N (1999) A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1. J Clin Invest 103(1):97–106
Roos D, Meischl C, de Boer M, Simsek S, Weening RS, Sanal O et al (2002) Genetic analysis of patients with leukocyte adhesion deficiency: genomic sequencing reveals otherwise undetectable mutations. Exp Hemat 30(3):252–261
Tone Y, Wada T, Shibata F, Toma T, Kasahara Y, Koizumi S, Yachie A (2007) Somatic revertant mosaicism in a patient with leukocyte adhesion deficiency type 1. Blood 109(3):1182–1184
Uzel G, Ing E, Rosenzweig SD, Hsu AP et al (2008) Reversion mutations in patients with leukocyte adhesion deficiency type 1 (LAD-1). Blood 111(1):209–218
Lorusso F, Kong D, Jalil AK, Sylvestre C, Tan SL, Ao A (2006) Preimplantation genetic diagnosis of leukocyte adhesion deficiency type I. Fertil Steril 85(2):e415–e498
Thomas C, Le Deist F, Cavazzana-Calvo M, Benkerrou M, Haddad E, Blanche S, Hartmann W, Friedrich W, Fischer A (1995) Results of allogeneic bone marrow transplantation in patients with leukocyte adhesion deficiency. Blood 86(4):1629–1635
Bauer TR, Hickstein DD (2000) Gene therapy for leukocyte adhesion deficiency. Curr Opin Mol Ther 2(4):383–388
Bauer TR, Allen JM, Hai M, Tuschong LM et al (2008) Successful treatment of canine leukocyte adhesive deficiency by foamy virus vectors. Nat Med 14(1):93–97
Etzioni A, Frydman M, Pollack S, Avidor I et al (1992) Brief report: recurrent severe infections caused by a novel leukocyte adhesion deficiency. N Engl J Med 327(25):1789–1792
Yakubenia S, Wild MK (2006) Leukocyte adhesion deficiency II. Advances and open questions. FEBS J 273(19):4390–4398
Wild MK, John K, Marquardt T, Vestweber D (2002) Leukocyte adhesion deficiency II: therapy and genetic defect. Cells Tissues Organs 172(3):161–173
Etzioni A, Gershoni-Baruch R, Pollack S, Shehadeh N (1998) Leukocyte adhesion deficiency type II: long-term follow-up. J Allergy Clin Immunol 102(2):323–324
Karsan A, Cornejo CJ, Winn RK, Schwartz BR, Way W, Lannir N, Gershoni-Baruch R, Etzioni A, Ochs HD, Harlan JM (1998) Leukocyte adhesion deficiency type II is a generalized defect of de novo GDP- fucose biosynthesis. Endothelial cell fucosylation is not required for neutrophil rolling on human nonlymphoid endothelium. J Clin Invest 101(11):2438–2445
Lubke T, Marquardt T, von Figura K, Korner C (1999) A new type of carbohydrate-deficient glycoprotein syndrome due to a decreased import of GDP-fucose into the Golgi. J Biol Chem 274(1):25986–25989
Lubke T, Marquardt T, Etzioni A, Hartmann E, von Figura K, Korner C (2001) Complementation cloning identifies CDG-IIc, a new type of congenital disorders of glycosylation, as a GDP-fucose transporter deficiency. Nat Genet 28(1):73–76
Helmus Y, Denecke J, Yakubenia S, Robinson P et al (2006) Leukocyte adhesion deficiency II patients with a dual defect of the GDP-fucose transporter. Blood 107(10):3959–3966
Hellbrush CC, Sperandis M, Frommhold D et al (2007) Golgi GDP-fucose transporter deficient mice mimic congenital disorder of glycozylation IIc/leukocyte adhesion deficiency II. J Biol Chem 282(14):10762–10772
Sturla L, Rampal R, Haltiwanger RS, Fruscione F, Etzioni A, Ronetti M (2003) Differential terminal fucosylation of N-linked glycans versus protein O-fucosylation in LAD II (CDG IIc). J Biol Chem 278(29):21559–21565
Luo Y, Haltiwanger RS (2005) O-fucosylation on Notch occur in the endoplasmic reticulum. J Biol Chem 280(12):11289–11294
Marquardt T, Luhn K, Srikrishna G, Freeze HH, Harms E, Vestweber D (1999) Correction of leukocyte adhesion deficiency type II with oral fucose. Blood 94(12):3976–3985
Etzioni A, Tonetti M (2000) Fucose supplementation in leukocyte adhesion deficiency type II. Blood 95(11):3641–3643
Alon R, Aker M, Feigelson S, Sokolovsky-Eisenberg M, Staunton DE, Cinamon G, Grabovsky V, Shamri R, Etzioni A (2003) 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 101(11):4437–4445
Alon R, Etzioni A (2003) LAD III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol 24(10):561–566
Kuijpers TW, Van Lier RA, Hamann D, de Boer M, Thung LY, Weening RS, Verhoeven AJ, Roos D (1997) Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta 2 integrins. J Clin Invest 100(7):1725–1733
Harris ES, Shigeoka AO, Li W, Adams RH, Prescott SM, McIntyre TM, Zimmerman GA, Lorant DE (2001) A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta1 and beta2 integrins. Blood 97(3):767–776
MacDowall A, Inwald D, Leitinger B, Jones A, Leisner R, Klein N, Hogg N (2003) A novel form of intregrin dysfunction involving beta 1, beta2 and beta 3 integrins. J Clin Invest 111(1):51–60
Kinashi T, Aker M, Sokolovsky-Eisenberg M, Grabovsky V, Tanaka C, Shamri R, Feigelson S, Etzioni A, Alon R (2004) LAD III, a leukocyte adhesion deficiency syndrome associated with defective Rap-1 activation and impaired stabilization of integrin bonds. Blood 103(3):1033–1036
Bos JL, de Rooij J, Reedquist KA (2001) Rap-1 signalling: adhering to new models. Nat Rev Mol Cell Biol 2(5):369–377
Crittenden JR, Bergmeier W, Zhang Y, Piffath CL et al (2004) CalDAG-GEFI integrates signalling for platelet aggregation and thrombus formation. Nat Med 10(9):982–986
Bergmeier W, George T, Wang HW et al (2007) Mice Lacking the signalling molecule CalDAG-GEF1 represent a model for leukocyte adhesion deficiency type III. JCI 117(6):1699–1707
Mory A, Feigelson SW, Yarali N (2008) Kindlin-3 a new gene involved in the pathogenesis of LAD III. Blood 112(6):2591
Kuijpers TW, van de Vijver E, Weternman MAJ et al (2009) LAD-1/variant syndrome is caused by mutations in FERMT3. Blood, in press. doi:10.1182/blood-2008-10-182154
Larjava H, Plow EF, Wu C (2008) Kindlines: essential regulators of integrin signalling and cell-matrix adhesion. EMBO 9(12):1203–1208
Moser M, Bauer M, Schmid S et al (2009) Kindlin 3 is required for beta 2 integrin mediated leukocyte Adhesion to endothelial cells. Nat Med 15(3):300–305
Svensson L, Howarth K, McDowall A et al (2009) Leukocyte adhesion deficiency III is caused by Mutations in Kindlin # affecting integrin activation. Nat Med 15(3):306–312
Malinin NI, Zhang L, Choi J et al (2009) A point mutation in Kindlin 3 ablates activation of three Subfamilies in humans. Nat Med 15(3):313–318
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Etzioni, A. Defects in the Leukocyte Adhesion Cascade. Clinic Rev Allerg Immunol 38, 54–60 (2010). https://doi.org/10.1007/s12016-009-8132-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12016-009-8132-3