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1/6. A novel CD18 genomic deletion in a patient with severe leucocyte adhesion deficiency: a possible CD2/lymphocyte function-associated antigen-1 functional association in humans.

    Leucocyte adhesion deficiency (LAD) is an autosomal-recessive genetic disease that is characterized clinically by severe bacterial infections and caused by mutations in the CD18 gene that codes for the beta2 integrin subunit. A patient with a severe LAD phenotype was studied and the molecular basis of the disease was identified as a single homozygous defect in a Herpes virus saimiri (HVS)-transformed T-cell line. The defect identified involves a deletion of 171 bp in the cDNA that encodes part of the proteic extracellular domain. This genetic abnormality was further studied at the genomic dna level and found to consist of a deletion of 169 bp (from -37 of intron 4 to 132 of exon 5), which abolishes the normal splicing and results in the total skipping of exon 5. The 171-bp shortened 'in-frame' mRNA not only resulted in the absence of CD18 expression on the cell surface but also in its absence in the cytoplasm of HVS T-cell lines. Functionally, the LAD-derived HVS T-cell lines showed a severe, selective T-cell activation impairment in the CD2 (but not in the CD3) pathway. This defect was not reversible when exogenous interleukin-2 (IL-2) was added, suggesting that there is also a functional interaction of the lymphocyte function-associated antigen-1 (LFA-1) protein in the CD2 signal transduction pathway in human T cells, as has been previously reported in mice and in the human Papillon-Lefevre syndrome. Thus, HVS transformation is not only a suitable model for T-cell immunodeficiency studies and characterization, but is also a good system for investigating the immune system in pathological conditions. It may also be used in the future in cellular models for in vitro gene-therapy trials.
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keywords = bacterial infection
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2/6. Leukocyte adhesion deficiency (LAD) II.

    The occurrence of recurrent bacterial infections, neutrophil motility dysfunction and normal expression of beta 2 integrins (CD18) in two unrelated children suggested an as yet undescribed adhesion deficiency. The fact that both children exhibited the rare Bombay blood group and were Lewis negative, each involving carbohydrates with different fucose linkages, suggested a possible defect in the fucose-containing ligand for E- and p-selectin, sialyl Lewis X (SLe(x)). Using a monoclonal anti-SLe(x) antibody, we did not detect expression of SLe(x) on the neutrophils of the patients. Adhesion of neutrophils to endothelial cells activated with interleukin-1 beta or histamine was markedly decreased ( < 5% of control). The observation that the neutrophils did not bind to recombinant e-selectin and purified p-selectin confirmed the SLe(x) deficiency as the basis for adhesion deficiency. Using several in vivo techniques, we were able to show that neutrophil rolling, the first step in their adhesion, is markedly decreased, and therefore neutrophil emigration through the endothelium and arrival at site of inflammation is significantly diminished (1-2% of normal). Low binding of fucose-specific lectins to the patients' B lymphocytes transformed with Epstein-Barr virus was observed, while the binding of mannose-specific lectins was normal, providing further evidence for a general fucose deficiency as the primary defect. The existence of the patients and their deficiency emphasizes the essential role of the endothelial cell selectins and their ligand, SLe(x), in recruitment of neutrophils to sites of infection.
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keywords = bacterial infection
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3/6. Leukocyte adhesion deficiency type 1 (LAD-1)/variant. A novel immunodeficiency syndrome characterized by dysfunctional beta2 integrins.

    Leukocyte adhesion deficiency (LAD) is characterized by the inability of leukocytes, in particular neutrophilic granulocytes, to emigrate from the bloodstream towards sites of inflammation. Infectious foci are nonpurulent and may eventually become necrotic because of abnormal wound healing. LAD-1 is characterized by the absence of the beta2 integrins (CD11/CD18) on leukocytes. When expression is completely absent, patients often die within the first year. However, low levels of beta2 expression may result in a milder clinical picture of recurrent infection, which offers a better prognosis. In this paper, we describe the in vivo and in vitro findings on a patient with clinical features of a mild LAD-1 disorder, i.e., suffering from bacterial infections without apparent pus formation in the presence of a striking granulocytosis, showing no delayed-type hypersensitivity reaction upon skin testing, no specific antibody generation, but normal in vitro T cell proliferation responses after immunization. Expression levels of CD11/CD18 proteins were completely normal, but leukocyte activation did not result in CD11/ CD18 activation and high-avidity ligand-binding. in vitro chemotaxis and endothelial transmigration of the neutrophils as well as leukocyte aggregation responses were almost absent. On the other hand, beta1 and beta3 integrin-mediated adhesion functions were completely normal. During follow-up, a bleeding tendency related to decreased beta3 activation became clinically apparent, different from previously described cellular adhesion molecule variants. Therefore, this is the first well-documented case of a clinical combined immunodeficiency syndrome that results from nonfunctional CD11/CD18 molecules, and thus designated LAD-1/ variant.
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keywords = bacterial infection
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4/6. Retroviral-mediated gene transfer of the leukocyte integrin CD18 into peripheral blood CD34 cells derived from a patient with leukocyte adhesion deficiency type 1.

    Leukocyte adhesion deficiency or LAD is a congenital immunodeficiency disease characterized by recurrent bacterial infections in which the leukocytes from affected children fail to adhere to endothelial cells and migrate to the site of infection due to heterogeneous defects in the leukocyte integrin CD18 subunit. To assess the feasibility of human gene therapy of LAD, we transduced granulocyte colony-stimulating factor (G-CSF)-mobilized, CD34 peripheral blood stem cells derived from a patient with the severe form of LAD using supernatant from the retroviral vector PG13/LgCD18. The highest transduction frequencies (31%) were found after exposure of the cells to retroviral vector on a substrate of recombinant fibronectin fragment CH-296 in the presence of growth factors interleukin-3 (IL-3), IL-6, and stem cell factor. When the phenotype of the transduced cells was monitored by fluorescence-activated cell sorting following in vitro differentiation with growth factors G-CSF and granulocyte-macrophage CSF (GM-CSF), CD11a surface expression was detected immediately after transduction. CD11b and CD11c were expressed at low levels immediately following transduction, but increased over 3 weeks in culture. Adhesion of the transduced cells was nearly double that of nontransduced cells in a cell adhesion assay using human umbilical vein endothelial cells. Transduced cells also demonstrated the ability to undergo a respiratory burst in response to opsonized zymosan, a CD11/CD18-dependent ligand. These experiments show that retrovirus-mediated gene transfer of the CD18 subunit complements the defect in LAD CD34 cells resulting in CD11/CD18 surface expression, and that the differentiated myelomonocytic cells derived from the transduced LAD CD34 cells display CD11/CD18-mediated adhesion function. These results indicate that ex vivo gene transfer of CD18 into LAD CD34 cells, followed by re-infusion of the transduced cells, may represent a therapeutic approach to LAD.
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keywords = bacterial infection
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5/6. A novel leukocyte adhesion deficiency caused by expressed but nonfunctional beta2 integrins Mac-1 and LFA-1.

    In the leukocyte adhesion deficiency (LAD)-1 syndrome, there is diminished expression of beta2(CD18) integrins. This is caused by lesions in the beta2-subunit gene and gives rise to recurrent bacterial infections, impaired pus formation, and poor wound healing. We describe a patient with clinical features compatible with a moderately severe phenotype of LAD-1 but who expresses the beta2 integrins lymphocyte function- associated molecule (LFA)-1 and Mac-1 at 40%-60% of normal levels. This level of expression should be adequate for normal integrin function, but both the patient's Mac-1 on neutrophils and LFA-1 on T cells failed to bind ligands such as fibrinogen and intercellular adhesion molecule (ICAM)-1, respectively, or to display a beta2-integrin activation epitope after adhesion-inducing stimuli. Unexpectedly, divalent cation treatment induced the patient's T cells to bind to ICAM-2 and ICAM-3. Sequencing of the patient's two CD18 alleles revealed the mutations S138P and G273R. Both mutations are in the beta2-subunit conserved domain, with S138P a putative divalent cation coordinating residue in the metal ion-dependent adhesion site (MIDAS) motif. After K562 cell transfection with alpha subunits, the mutated S138P beta subunit was coexpressed but did not support function, whereas the G273R mutant was not expressed. In summary, the patient described here exhibits failure of the beta2 integrins to function despite adequate levels of cell-surface expression.
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keywords = bacterial infection
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6/6. pyoderma gangrenosum in a child with congenital partial deficiency of leucocyte adherence glycoproteins.

    Congenital deficiency of beta 2 integrin leucocyte adhesion molecules is a rare immunodeficiency and is often fatal. neutrophils are unable to bind to ligands on the endothelium, and so cannot leave the circulation during inflammation or infection. When leucocyte adhesion deficiency (LAD) is caused by abnormally low expression of beta 2 integrins, it is termed LAD type 1. We describe a 5-year-old girl with a history of recurrent bacterial infections since early childhood who developed necrotic skin ulcers resembling pyoderma gangrenosum and a persistent circulating neutrophilia. Histologically, the lesions showed deep ulceration with a diffuse lymphohistiocytic infiltrate, but with a relative sparsity of neutrophils. Subsequent investigation revealed a complete absence of CD11a/CD18 beta 2 integrins on the surface of the patient's neutrophils, confirming the diagnosis of LAD type 1. The ulcers responded to treatment with oral prednisolone and colchicine.
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ranking = 1
keywords = bacterial infection
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