leukocyte adhesion deficiency syndrome

Summary

Summary: Rare, autosomal recessive disorder caused by deficiency of the beta 2 integrin receptors (RECEPTORS, LEUKOCYTE-ADHESION) comprising the CD11/CD18 family of glycoproteins. The syndrome is characterized by abnormal adhesion-dependent functions, especially defective tissue emigration of neutrophils, leading to recurrent infection.

Top Publications

  1. McDowall A, Inwald D, Leitinger B, Jones A, Liesner R, Klein N, et al. A novel form of integrin dysfunction involving beta1, beta2, and beta3 integrins. J Clin Invest. 2003;111:51-60 pubmed
  2. Kinashi T, Aker M, Sokolovsky Eisenberg M, Grabovsky V, Tanaka C, Shamri R, 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 pubmed
    ..This is a first report of an inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function, we herein term it "LAD-III."..
  3. Alon R, Etzioni A. LAD-III, a novel group of leukocyte integrin activation deficiencies. Trends Immunol. 2003;24:561-6 pubmed
    ..Here, the mechanisms by which GPCRs might regulate leukocyte and platelet integrins are outlined with respect to this new family of LAD cases. We propose to term this the LAD-III family...
  4. Mizgerd J, Kubo H, Kutkoski G, Bhagwan S, Scharffetter Kochanek K, Beaudet A, et al. Neutrophil emigration in the skin, lungs, and peritoneum: different requirements for CD11/CD18 revealed by CD18-deficient mice. J Exp Med. 1997;186:1357-64 pubmed
    ..Whereas CD11/CD18 complexes are essential to the dermal emigration of neutrophils during acute dermatitis, CD18-/- mutant mice demonstrate surprising alternative pathways for neutrophil emigration during pneumonia or peritonitis...
  5. Arnaout M. Leukocyte adhesion molecules deficiency: its structural basis, pathophysiology and implications for modulating the inflammatory response. Immunol Rev. 1990;114:145-80 pubmed
  6. Alon R, Aker M, Feigelson S, Sokolovsky Eisenberg M, Staunton D, Cinamon G, 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 pubmed
    ..This syndrome is the first example of a human integrin-activation deficiency associated with defective GPCR stimulation of integrin avidity at subsecond contacts, a key step in leukocyte arrest on vascular endothelium under shear flow...
  7. Smith P, Myers J, Rogers C, Zhou L, Petryniak B, Becker D, et al. Conditional control of selectin ligand expression and global fucosylation events in mice with a targeted mutation at the FX locus. J Cell Biol. 2002;158:801-15 pubmed
    ..Conditional control of fucosylation in FX(-/-) mice identifies cellular fucosylation events as essential concomitants to fertility, early growth and development, and leukocyte adhesion...
  8. Beals C, Edwards A, Gottschalk R, Kuijpers T, Staunton D. CD18 activation epitopes induced by leukocyte activation. J Immunol. 2001;167:6113-22 pubmed
    ..Collectively, these neoepitope Abs identify a subpopulation of LFA-1 most likely with high affinity for ICAM-1 and necessary for LFA-1 function...
  9. Luhn K, Wild M, Eckhardt M, Gerardy Schahn R, Vestweber D. The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. Nat Genet. 2001;28:69-72 pubmed
    ..Thus, we have identified the first putative GDP-fucose transporter, which has been highly conserved throughout evolution. A point mutation in its gene is responsible for the disease in this patient with LAD II...

More Information

Publications62

  1. Hogg N, Bates P. Genetic analysis of integrin function in man: LAD-1 and other syndromes. Matrix Biol. 2000;19:211-22 pubmed
    ..The majority of the beta subunit mutations are in the conserved N-terminal region known as the betaI domain. It is suggested that this region participates in alphabeta heterodimer formation...
  2. Becker D, Lowe J. Leukocyte adhesion deficiency type II. Biochim Biophys Acta. 1999;1455:193-204 pubmed
    ..The genetic lesion in LAD II that accounts for the generalized fucosylation defect in LAD II patients remains to be determined...
  3. Frenette P, Mayadas T, Rayburn H, Hynes R, Wagner D. Susceptibility to infection and altered hematopoiesis in mice deficient in both P- and E-selectins. Cell. 1996;84:563-74 pubmed
    ..Our results show that the absence of endothelial selectins severely affects leukocyte homeostasis and indicate that these two selectins are as important for normal leukocyte function as are the leukocyte beta2 integrins...
  4. Karsan A, Cornejo C, Winn R, Schwartz B, Way W, Lannir N, et al. 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. 1998;101:2438-45 pubmed
  5. Etzioni A, Alon R. Leukocyte adhesion deficiency III: a group of integrin activation defects in hematopoietic lineage cells. Curr Opin Allergy Clin Immunol. 2004;4:485-90 pubmed
    ..The clinical manifestations and molecular basis of this syndrome and related cases will be reviewed...
  6. Wilson J, Ping A, Krauss J, Mayo Bond L, Rogers C, Anderson D, et al. Correction of CD18-deficient lymphocytes by retrovirus-mediated gene transfer. Science. 1990;248:1413-6 pubmed
  7. Uzel G, Kleiner D, Kuhns D, Holland S. Dysfunctional LAD-1 neutrophils and colitis. Gastroenterology. 2001;121:958-64 pubmed
    ..The existence of active IBD in the presence of dysfunctional CD18/CD11(a-b) intercellular adhesion molecules (ICAM-1) interaction is relevant to the proposed targeting of ICAM-1 for the treatment of Crohn's disease...
  8. Jabbari Azad F, Ardalan M, Hoseinpoor Rafati A, Sotoudeh S, Pourpak Z. Osteomyelitis in leukocyte adhesion deficiency type 1 syndrome. J Infect Dev Ctries. 2010;4:175-8 pubmed
  9. Sun X, Rozenfeld R, Qu X, Huang W, Gonzalez Crussi F, Hsueh W. P-selectin-deficient mice are protected from PAF-induced shock, intestinal injury, and lethality. Am J Physiol. 1997;273:G56-61 pubmed
    ..Thus P-selectin plays an important role in PAF-induced injury in mice, and the selectins and the integrin-ICAM-1 system work in concert to mediate the inflammatory response to PAF in vivo...
  10. Simon A, Pillai S, Raghupathy P, Chandy M. Leucocyte adhesion deficiency-1. Indian Pediatr. 2002;39:963-6 pubmed
  11. Reumaux D, Kuijpers T, Hordijk P, Duthilleul P, Roos D. Involvement of Fcgamma receptors and beta2 integrins in neutrophil activation by anti-proteinase-3 or anti-myeloperoxidase antibodies. Clin Exp Immunol. 2003;134:344-50 pubmed
    ..We therefore conclude that ligation of beta2 integrins rather than adherence per se is essential for this activation, and that TNF-alpha or GM-CSF is needed for priming but not for adherence...
  12. Nagahata H, Higuchi H, Yamashiki N, Yamaguchi M. Analysis of the functional characteristics of L-selectin and its expression on normal and CD18-deficient bovine neutrophils. Immunol Cell Biol. 2000;78:264-71 pubmed
    ..The degree of L-selectin expression on neutrophils was correlated with the intracellular signalling events and the related superoxide production...
  13. Gorski J, Westbrook A. Use of differential reinforcement to treat medical non-compliance in a paediatric patient with leukocyte adhesion deficiency. Pediatr Rehabil. 2002;5:29-35 pubmed
    ..During the last week of his hospitalization, the use of his crutches was task analysed and included in his reinforcement programme using a changing criterion design. His average use of his crutches also improved to 80%...
  14. Sokolic R, Bauer T, Gu Y, Hai M, Tuschong L, Burkholder T, et al. Nonmyeloablative conditioning with busulfan before matched littermate bone marrow transplantation results in reversal of the disease phenotype in canine leukocyte adhesion deficiency. Biol Blood Marrow Transplant. 2005;11:755-63 pubmed
    ..These results indicate that a nonmyeloablative conditioning regimen with chemotherapy alone is capable of generating stable mixed chimerism and reversal of the disease phenotype in CLAD...
  15. Mellouli F, Ksouri H, Barbouche R, Maamer M, Hamed L, Hmida S, et al. Successful treatment of Fusarium solani ecthyma gangrenosum in a patient affected by leukocyte adhesion deficiency type 1 with granulocytes transfusions. BMC Dermatol. 2010;10:10 pubmed publisher
  16. van Vliet D, Brandsma A, Hartwig N. [Leukocyte-adhesion deficiency: a rare disorder of inflammation]. Ned Tijdschr Geneeskd. 2004;148:2496-500 pubmed
    ..These conditions already become manifest in childhood. Therapy is generally symptomatic and consists mainly of the prevention and treatment of infection. Cure is sometimes possible by means of allogenic bone-marrow transplantation...
  17. Yakubenia S, Wild M. Leukocyte adhesion deficiency II. Advances and open questions. FEBS J. 2006;273:4390-8 pubmed
    ..In this review we focused on the current controversies, and open questions that have arisen from recent studies on the genetic defect, therapy and the basis of psychomotor defects in LAD II...
  18. Ganesh A, Al Zuhaibi S, Bialasiewicz A, Al Abri R, Ahmed S, Al Tamemi S, et al. Necrotizing Pseudomonas infection of the ocular adnexa in an infant with leukocyte adhesion defect. J Pediatr Ophthalmol Strabismus. 2007;44:199-200 pubmed
  19. 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-S56 pubmed publisher
    ..We present the data on outcome for primary immunodeficiency transplantation at King Faisal Specialist Hospital from 1993 to 2006...
  20. Poursharifi P, Saghiri R, Ebrahimi Rad M, Nazem H, Pourpak Z, Moin M, et al. Adenosine deaminase in patients with primary immunodeficiency syndromes: the analysis of serum ADA1 and ADA2 activities. Clin Biochem. 2009;42:1438-43 pubmed publisher
    ..We aimed to investigate the activity of ADA and its isoenzymes in serum of patients with various primary immunodeficiency (PID) syndromes...
  21. Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, et al. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009;15:306-12 pubmed publisher
    ..Notably, transfection of the subjects' lymphocytes with KINDLIN3 complementary DNA but not CALDAGGEF1 cDNA reverses the LAD-III defect, restoring integrin-mediated adhesion and migration...
  22. Kobayashi S, Sato R, Abe Y, Inanami O, Yasui H, Omoe K, et al. Canine neutrophil dysfunction caused by downregulation of beta2-integrin expression without mutation. Vet Immunol Immunopathol. 2009;130:187-96 pubmed publisher
  23. Nagahata H, Hagiwara K, Kasamatsu M, Higuchi H, Kurosawa T. Cytokine profile of a Holstein calf with bovine leukocyte adhesion deficiency during the acute-phase inflammatory response. J Vet Med Sci. 2002;64:1141-3 pubmed
  24. Bimstein E, Wignall W, Cohen D, Katz J. Root surface characteristics of children teeth with periodontal diseases. J Clin Pediatr Dent. 2008;32:101-4 pubmed
    ..Cementum anomalies may facilitate the establishment and progress of periodontitis in children...
  25. Wild M, Luhn K, Marquardt T, Vestweber D. Leukocyte adhesion deficiency II: therapy and genetic defect. Cells Tissues Organs. 2002;172:161-73 pubmed
    ..Thus, LAD II represents the first developmental and immune defect that is based on a malfunctioning nucleotide sugar transporter...
  26. Uzel G, Tng E, Rosenzweig S, Hsu A, Shaw J, Horwitz M, et al. Reversion mutations in patients with leukocyte adhesion deficiency type-1 (LAD-1). Blood. 2008;111:209-18 pubmed
    ..The discovery of 3 cases of reversion mutations in LAD-1 at one center suggests that this may be a relatively common event in this rare disease...
  27. Nagahata H, Higuchi H, Teraoka H, Takahashi K, Takahashi K, Kuwabara M, et al. Decreased apoptosis of beta 2- integrin-deficient bovine neutrophils. Immunol Cell Biol. 2004;82:32-7 pubmed
  28. Gabius H, Andre S, Kaltner H, Siebert H. The sugar code: functional lectinomics. Biochim Biophys Acta. 2002;1572:165-77 pubmed
  29. Pfeiffer I, Brenig B. Frequency of the canine leucocyte adhesion deficiency (CLAD) mutation among Irish red setters in Germany. J Anim Breed Genet. 2005;122:140-2 pubmed
    ..The present report describes the analysis of the single nucleotide polymorphism in 289 Irish red setters by DNA sequencing. The frequency of CLAD carriers in Germany is 11%...
  30. Heale J, Pollard A, Stokes R, Simpson D, Tsang A, Massing B, et al. Two distinct receptors mediate nonopsonic phagocytosis of different strains of Pseudomonas aeruginosa. J Infect Dis. 2001;183:1214-20 pubmed
    ..The impact of lung infection with P. aeruginosa may be determined, in part, by the phagocytic receptor that mediates ingestion...
  31. Tokunaga M, Miyamura K, Ohashi H, Ishiwada N, Terakura S, Ikeguchi M, et al. Successful nonmyeloablative bone marrow transplantation for leukocyte adhesion deficiency type I from an unrelated donor. Int J Hematol. 2007;86:91-5 pubmed
    ..Twenty one months after transplantation, she is well with a Karnofsky score of 100. Thus, nonmyeloablative transplantation is considered a feasible method for LAD-I...
  32. Lorusso F, Kong D, Jalil A, Sylvestre C, Tan S, Ao A. Preimplantation genetic diagnosis of leukocyte adhesion deficiency type I. Fertil Steril. 2006;85:494.e15-8 pubmed
    ..To describe the application of preimplantion genetic diagnosis (PF to a carrier couple for leukocyte adhesion deficiency type I disease (LAD-1), to achieve a healthy pregnancy...
  33. Malawista S, De Boisfleury Chevance A, Brown E, Boxer L, Law S. Chemotaxis of non-compressed blood polymorphonuclear leukocytes from an adolescent with severe leukocyte adhesion deficiency. Am J Hematol. 2003;73:115-20 pubmed
    ..These findings indicate that not all patients with severe LAD are candidates for early bone marrow transplantation...
  34. Elloumi H, Holland S. Diagnostic assays for chronic granulomatous disease and other neutrophil disorders. Methods Mol Biol. 2007;412:505-23 pubmed publisher
    ..The assays are relatively simple to perform, cost-effective, and can be performed with equipment available in most laboratories...
  35. Montero C, Stock F, Murray P. Mechanisms of resistance to daptomycin in Enterococcus faecium. Antimicrob Agents Chemother. 2008;52:1167-70 pubmed publisher
    ..clonal emergence of daptomycin-resistant Enterococcus faecium strains isolated from a patient with leukocyte adhesion deficiency syndrome. The resistance mechanism in these strains is independent of either equivalent point mutations ..
  36. Hart T, Atkinson J. Mendelian forms of periodontitis. Periodontol 2000. 2007;45:95-112 pubmed
  37. Debenham S, Millington A, Kijast J, Andersson L, Binns M. Canine leucocyte adhesion deficiency in Irish red and white setters. J Small Anim Pract. 2002;43:74-5 pubmed
    ..Routine testing by breeders to identify carrier animals will enable the eradication of CLAD from the Irish red and white setter population...
  38. Bauer T, Hai M, Tuschong L, Burkholder T, Gu Y, Sokolic R, et al. Correction of the disease phenotype in canine leukocyte adhesion deficiency using ex vivo hematopoietic stem cell gene therapy. Blood. 2006;108:3313-20 pubmed
  39. Bartunkova J, Maly P, Smetana K, Sediva A, Klubal R, Mayerova D, et al. Reduced phagocytic activity of polymorphonuclear leukocytes in alpha(1,3) fucosyltransferase VII-deficient mice. APMIS. 2000;108:409-16 pubmed
    ..In conclusion, the lack of Fuc-TVII activity leads to several morphological and functional abnormalities without an impact on survival rate...
  40. Bauer T, Creevy K, Gu Y, Tuschong L, Donahue R, Metzger M, et al. Very low levels of donor CD18+ neutrophils following allogeneic hematopoietic stem cell transplantation reverse the disease phenotype in canine leukocyte adhesion deficiency. Blood. 2004;103:3582-9 pubmed
    ..These results demonstrate the value of a disease-specific, large-animal model for identifying the lowest therapeutic level required for successful cellular and gene therapy...
  41. Niederman R, Westernoff T, Lee C, Mark L, Kawashima N, Ullman Culler M, et al. Infection-mediated early-onset periodontal disease in P/E-selectin-deficient mice. J Clin Periodontol. 2001;28:569-75 pubmed
    ..Increased susceptibility to periodontal disease is therefore thought to result from multiple risk factors...
  42. Nelson E, Tuschong L, Hunter M, Bauer T, Burkholder T, Hickstein D. Lentiviral vectors incorporating a human elongation factor 1alpha promoter for the treatment of canine leukocyte adhesion deficiency. Gene Ther. 2010;17:672-7 pubmed publisher
  43. Scharffetter Kochanek K, Lu H, Norman K, van Nood N, Munoz F, Grabbe S, et al. Spontaneous skin ulceration and defective T cell function in CD18 null mice. J Exp Med. 1998;188:119-31 pubmed
    ..The null mice are useful for delineating the functions of CD18 in vivo...
  44. Roosien F, de Kuiper P, de Rijk D, Roos E. Invasive and metastatic capacity of revertants of LFA-1-deficient mutant T-cell hybridomas. Cancer Res. 1990;50:3509-13 pubmed
    ..These results provide further evidence for an important role of LFA-1 in invasion and metastasis of mouse T-cell hybridomas...
  45. Roos D, Meischl C, de Boer M, Simsek S, Weening R, Sanal O, et al. Genetic analysis of patients with leukocyte adhesion deficiency: genomic sequencing reveals otherwise undetectable mutations. Exp Hematol. 2002;30:252-61 pubmed
  46. Roos D, Law S. Hematologically important mutations: leukocyte adhesion deficiency. Blood Cells Mol Dis. 2001;27:1000-4 pubmed
    ..This article summarizes all known patient mutations and polymorphisms in these genes...
  47. Peters T, Sindrilaru A, Hinz B, Hinrichs R, Menke A, Al Azzeh E, et al. Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation. EMBO J. 2005;24:3400-10 pubmed
    ..Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing...
  48. Hidalgo A, Ma S, Peired A, Weiss L, Cunningham Rundles C, Frenette P. Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene. Blood. 2003;101:1705-12 pubmed
    ..The robust response to fucose despite a severely truncated transporter suggests alternative means to transport GDP-fucose into the Golgi complex...
  49. Creevy K, Bauer T, Tuschong L, Embree L, Silverstone A, Bacher J, et al. Mixed chimeric hematopoietic stem cell transplant reverses the disease phenotype in canine leukocyte adhesion deficiency. Vet Immunol Immunopathol. 2003;95:113-21 pubmed
    ..These results indicate that mixed hematopoietic chimerism reverses the clinical phenotype in CLAD and represents a potential therapeutic approach for the human disease leukocyte adhesion deficiency...
  50. Etzioni A, Sturla L, Antonellis A, Green E, Gershoni Baruch R, Berninsone P, et al. Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation. Am J Med Genet. 2002;110:131-5 pubmed
    ..Genotype/phenotype correlation studies show that the two different mutations are distinguished by differences in response to fucose supplementation and in the clinical phenotypes...
  51. Suliaman F, Jabbar M. The association of leukocyte adhesion defect type I and persistent hyperinsulinemic hypoglycemia of infancy in a Saudi Arabian family. Pediatr Hematol Oncol. 2002;19:429-32 pubmed
    ..Both had successful bone marrow transplants from identical siblings. One of the patients was found to have persistent hypoglycemia of infancy. The association of these two rare conditions has not been reported previously...
  52. Lausen B, Hougs L, Schejbel L, Heilmann C, Barington T. Human memory B cells transferred by allogenic bone marrow transplantation contribute significantly to the antibody repertoire of the recipient. J Immunol. 2004;172:3305-18 pubmed
    ..Thus, memory B cells were transferred from the donor, persisted for at least 9 mo in the recipient, and constituted the major part of the HibCP-specific repertoire...
  53. Sabnis H, Kirpalani A, Horan J, McDowall A, Svensson L, Cooley A, et al. Leukocyte adhesion deficiency-III in an African-American patient. Pediatr Blood Cancer. 2010;55:180-2 pubmed publisher
    ..She was successfully treated with allogeneic bone marrow transplant using a reduced intensity-conditioning regimen. Mutations in KINDLIN-3 have been described in LAD-III but the mutations in KINDLIN-3 in her case are unique...