Leukocyte Adhesion Deficiencies: Molecular Basis, Clinical Findings, and Therapeutic Options
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 β 2-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 from a less severe form of disease, resembling the moderate phenotype of LAD I. LAD III emphasizes the importance of the integrin activation phase in the adhesion cascade. Although the primary defect is still unknown, it is clear that 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.
KeywordsIntegrin Activation Leukocyte Adhesion Deficiency Marked Leukocytosis Moderate Phenotype Adhesion Cascade
Unable to display preview. Download preview PDF.
- Alon, R., Aker, M., Feigelson, S., Sokolovsky-Eisenberg, M., Staunton, D.E., Cinamon, G., Grabovsky, V., Shamri, R. and 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, 4437–4445.CrossRefPubMedGoogle Scholar
- Anderson, D.C. and Smith, C.W. (2001). Leukocyte adhesion deficiency and other disorders of leukocyte adherence and motility. New York, McGraw-Hill.Google Scholar
- Bauer, T.R., Jr., Hai, M., Tuschong, L.M., Burkholder, T.H., Gu, Y.C., Sokolic, R.A., Ferguson, C., Dunbar, C.E. and Hickstein, D.D. (2006) Correction of the disease phenotype in canine leukocyte adhesion deficiency using ex vivo hematopoietic stem cell gene therapy. Blood 108, 3313–3320.CrossRefPubMedGoogle Scholar
- Fischer, A., Lisowska-Grospierre, B., Anderson, D. and Springer, T. (1988) Leukocyte adhesion deficiency: molecular basis and functional consequences. Immunol. Rev. 1, 39–54.Google Scholar
- Karsan, A., Cornejo, C.J., Winn, R.K., Schwartz, B.R., Way, W., Lannir, N., Gershoni-Baruch, R., Etzioni, A., Ochs, H.D. and Harlan, J.M. (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, 2438–2445.CrossRefPubMedGoogle Scholar
- Kinashi, T., Aker, M., Sokolovsky-Eisenberg, M., Grabovsky, V., Tanaka, C., Shamri, R., Feigelson, S., Etzioni, A. and Alon, R. (2004) LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds. Blood 103, 1033–1036.CrossRefPubMedGoogle Scholar
- Kuijpers, T.W., Van Lier, R.A., Hamann, D., de Boer, M., Thung, L.Y., Weening, R.S., Verhoeven, A.J. and Roos, D. (1997) Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins. J. Clin. Invest. 100, 1725–1733.CrossRefPubMedGoogle Scholar
- Lorusso, F., Kong, D., Jalil, A.K., Sylvestre, C., Tan, S.L. and Ao, A. (2006) Preimplantation genetic diagnosis of leukocyte adhesion deficiency type I. Fertil. Steril. 85, 494 e415–e498.Google Scholar
- Shamri, R., Grabovsky, V., Gauguet, J.M., Feigelson, S., Manevich, E., Kolanus, W., Robinson, M.K., Staunton, D.E., von Andrian, U.H. and Alon, R. (2005) Lymphocyte arrest requires instantaneous induction of an extended LFA-1 conformation mediated by endothelium-bound chemokines. Nat. Immunol. 6, 497–506.CrossRefPubMedGoogle Scholar
- von Andrian, U.H., Berger, E.M., Ramezani, L., Chambers, J.D., Ochs, H.D., Harlan, J.M., Paulson, J.C., Etzioni, A. and Arfors, K.E. (1993) In vivo behavior of neutrophils from two patients with distinct inherited leukocyte adhesion deficiency syndromes. J. Clin. Invest. 91, 2893–2897.CrossRefGoogle Scholar
- von Andrian, U.H. and Mackay, C.R. (2000) T cell function and migration. Two sides of the same coin. N. Engl. J. Med. 343, 1020–1034.Google Scholar
- Yakubenia, S. and Wild, M.K. (2006) Leukocyte adhesion deficiency II. Advances and open questions. FEBS J. 273, 4390–4398.Google Scholar