Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leucocyte adhesion deficiency is an immunodeficiency disease of autosomal recessive inheritance characterized by recurrent bacterial skin infections, impired pus formation and delayed wound healing. Leukocytes, including granulocytes and lymphocytes, from the LAD show defect in adhesion molecules of beta 2 integrin, LFA-1, Mac-1 and p150, 95, on its leukocyte membrane surface. This paper is a review article describing clinical features, leukocyte functions and molecular basis for the defective expression of the beta 2 integrin molecules in the LAD.
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PMID:[Leukocyte adhesion deficiency: its clinical and molecular analyses]. 815 39

Leukocyte adhesion deficiency type II (LAD II) is a rare genetic disease characterized by severe immunodeficiency which is related to defective expression in leukocytes of sialyl-Lewis X (SLeX), a fucosylated ligand for endothelial selectins. The molecular basis of LAD II is still unknown, but has been tentatively localized in the de novo pathway of GDP-L-fucose biosynthesis from GDP-D-mannose. Here, we demonstrate that in cell lysates from a LAD II patient, GDP-D-mannose-4,6-dehydratase (GMD), the first of the two enzymes of the pathway has a defective activity compared to control subjects. GMD in cell lysates from both parents showed intermediate activity levels. Cloning of GMD from patient and control lymphocytes ruled out any mutation affecting the amino acid GMD sequence and the purified recombinant proteins from both controls and the patient showed identical specific activities. Since the levels of immunoreactive GMD in cell lysates were comparable in the patient and in controls, the biochemical deficiency of intracellular GMD activity in LAD II seems to be due to mutation(s) affecting some still unidentified GMD-regulating protein.
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PMID:Defective intracellular activity of GDP-D-mannose-4,6-dehydratase in leukocyte adhesion deficiency type II syndrome. 966 31

Canine leukocyte adhesion deficiency (CLAD) is a fatal immunodeficiency disease found in Irish setters. The clinical manifestations of CLAD are very similar to LAD in humans and BLAD in cattle, which are both caused by mutations in ITGB2 encoding the leukocyte integrin beta-2 subunit (CD18). Sequence analysis of the ITGB2 coding sequence from a CLAD dog and a healthy control revealed a single missense mutation, Cys36Ser. This cysteine residue is conserved among all beta integrins, and the mutation most likely disrupts a disulfide bond. The mutation showed a complete association with CLAD in Irish setters and was not found in a sample of dogs from other breeds. The causative nature of this mutation was confirmed by transduction experiments using retroviral vectors and human LAD EBV B-cells. The normal canine CD18 formed heterodimers with the human CD11 subunit, whereas gene transfer of the mutant CD18 resulted in very low levels of CD11/CD18 expression. The identification of the causative mutation for CLAD now makes it possible to identify carrier animals with a simple diagnostic DNA test, and it forms the basis for using CLAD as a large animal model for the development and evaluation of clinical treatments for human LAD.
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PMID:A missense mutation in the beta-2 integrin gene (ITGB2) causes canine leukocyte adhesion deficiency. 1051 85

We describe a simple, noninvasive, and effective therapy for leukocyte adhesion deficiency type II (LAD II), a rare inherited disorder of fucose metabolism. This disorder leads to an immunodeficiency caused by the absence of carbohydrate-based selectin ligands on the surface of neutrophils as well as to severe psychomotor and mental retardation. The fucosylation defect in LAD II fibroblasts can be corrected by addition of L-fucose to the culture medium. This prompted us to initiate dietary fucose therapy on a patient with LAD II. Oral supplementation of fucose in this patient induced the expression of fucosylated selectin ligands on neutrophils and core fucosylation of serum glycoproteins. During 9 months of treatment, infections and fever disappeared, elevated neutrophil counts returned to normal, and psychomotor capabilities improved.
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PMID:Correction of leukocyte adhesion deficiency type II with oral fucose. 1087 54

For patients with well-characterized, rapidly fatal, nonmalignant immunodeficiency disorders, such as SCID, the decision to proceed with allogeneic SCT is clear-cut. For patients with many other disorders, this decision can be extremely difficult. Disorders such as LAD or CGD have a variable natural history. Each patient must be considered individually, with the risk for SCT-related morbidity and mortality carefully weighed against that of the underlying disease. Significant advances during the past 10 years have made SCT a much safer procedure. Use of nonmyeloablative conditioning regimens as a means of reducing toxicity of high-dose chemotherapy and irradiation hold great promise. Highly immunosuppressive, nonchemotherapeutic agents that inhibit graft rejection or GVHD by blocking the critical costimulatory component of the T-cell receptor-antigen interaction are beginning to emerge and may be ideal for SCT of nonmalignant diseases. Therefore, the risk-benefit equation must be reassessed each year as the severity of patients' disorders is better defined and techniques of SCT improve.
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PMID:Stem-cell transplantation for inherited immunodeficiency disorders. 1113 Oct 1

Bone marrow transplantation (BMT) is the treatment of choice in children affected by primary immunodeficiency (PID). Because only 10-15% of affected children have a familial HLA-identical donor alternative therapeutic options are BMT from a matched unrelated donor or an haploidentical BMT. In our experience only 40% of these children find a donor within the International Registry. Therefore, the remaining 50% children affected by PID are candidates for haploidentical BMT. Unfortunately, in PID other than sever-combined immunodeficiency (SCID), low engraftment rates have been reported because of minimal residual immunity. In order to enhance engraftment rate in haploidentical BMT in PID we suggest a protocol with addition of donor peripheral stem cells after mobilization with granulocyte colony-stimulating factor (G-CSF) (16 micrograms/kg for 5 days) and bone marrow cells. This procedure increases the cell load, which allows intensification of the conditioning regimen for induction of faster engraftment. The separation of CD34+ cells from leukapheresis products was achieved in the first 6 patients by the Isolex 300 system (Baxter) with a CD34+ cell purity range of 80-95% and in another three patients by the Clinimacs System (Miltenyi). The peripheral blood stem cells were cryopreserved until BMT, 15 days after G-CSF stimulation when the bone marrow was harvested, processed and T-cell depleted with Campath 1-M in the first 6 cases while the Clinimacs System was used in the remaining cases and no T-cell depletion was required. We included 9 patients in the study protocol: SCID (4), Omenn's syndrome (3), LAD (1) and CID (1). The mean value of peripheral CD34+ cells infused was 13.42 x 10(6)/kg and the mean CD3+ cells number was 0.385 x 10(5)/kg; the mean value of BM CD34+ cells infused was 10.62 x 10(6)/kg and the mean CD3+ cell number was 2.39 x 10(5)/kg. The mean number of infused CFU was 8.1 x 10(5)/kg for PBSC and 3.59 x 10(5)/kg for BM. The 9 patients achieved more than 0.5 x 10(9) peripheral blood neutrophils/L at a mean of 14.6 days (range: 6-22 days). One patient affected by SCID showed complete chimerism, but he died after BMT of systemic CMV infection; the other 8 patients are alive and well and 4 of them show complete chimerism in all cell lines. Split chimerism was documented in 2 SCID cases (CD3+ lymphocytes were of donor origin, monocytes were autologous and granulocytes were mainly autologous); 1 patient affected by Omenn's syndrome received 3 transplants (1 from the mother and 2 from the father, T-cells alone and bone marrow) and achieved engraftment with complete chimerism after the third transplant; the patient affected by LAD also received 3 transplants (2 bone marrow infusions and 1 PBSC infusion) achieving complete chimerism after the third one. In conclusion, the engraftment achieved in all treated patients, and the acceptable conditioning-related toxicity suggest that this approach could be successfully applied to children affected by PID and candidates for haploidentical BMT.
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PMID:Haploidentical peripheral blood and marrow stem cell transplantation in nine cases of primary immunodeficiency. 1126 23

Leukocyte adhesion deficiency II (LAD II) is characterized by the lack of fucosylated glycoconjugates, including selectin ligands, causing immunodeficiency and severe mental and growth retardation. No deficiency in fucosyltransferase activities or in the activities of enzymes involved in GDP-fucose biosynthesis has been found. Instead, the transport of GDP-fucose into isolated Golgi vesicles of LAD II cells appeared to be reduced. To identify the gene mutated in LAD II, we cloned 12 cDNAs from Caenorhabditis elegans, encoding multi-spanning transmembrane proteins with homology to known nucleotide sugar transporters, and transfected them into fibroblasts from an LAD II patient. One of these clones re-established expression of fucosylated glycoconjugates with high efficiency and allowed us to identify a human homolog with 55% identity, which also directed re-expression of fucosylated glycoconjugates. Both proteins were localized to the Golgi. The corresponding endogenous protein in LAD II cells had an R147C amino acid change in the conserved fourth transmembrane region. Overexpression of this mutant protein in cells from a patient with LAD II did not rescue fucosylation, demonstrating that the point mutation affected the activity of the protein. 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.
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PMID:The gene defective in leukocyte adhesion deficiency II encodes a putative GDP-fucose transporter. 1132 79

Leukocyte adhesion deficiency II (LAD II) is a rare congenital disease which is caused by a defect in fucosylation of glycoconjugates. Hypofucosylated structures include ligands for the selectin family of adhesion molecules. This results in a leukocyte adhesion defect causing an immunodeficiency. In addition, LAD II patients show severe mental and growth retardations suggesting a role of fucose in development. Recently, a LAD II patient was treated with oral supplementation of fucose. This simple therapy restored selectin ligands and corrected the immunodeficiency. However, in another patient the treatment protocol had no effect indicating that the biochemical defect in the latter patient is somewhat different. The genetic defect in LAD II has now been located to a gene encoding a GDP-fucose transporter which gates GDP-fucose into the Golgi where fucose is transferred onto glycoconjugates. Point mutations have been detected in this gene in several LAD II patients, which inactivate the transporter function. Thus, LAD II represents the first developmental and immune defect that is based on a malfunctioning nucleotide sugar transporter.
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PMID:Leukocyte adhesion deficiency II: therapy and genetic defect. 1247 46

Children with the genetic immunodeficiency disease leukocyte adhesion deficiency, or LAD, develop life-threatening bacterial infections as a result of the inability of their leukocytes to adhere to the vessel wall and migrate to the sites of infection. Recently, the canine counterpart to LAD, known as canine leukocyte adhesion deficiency, or CLAD, has been described in Irish setter dogs. This review describes how the clinical phenotype of dogs with CLAD closely parallels that of children with the severe deficiency phenotype of LAD, thus enabling the CLAD dog to provide a disease-specific, large-animal model for testing novel hematopoietic stem cell and gene therapy strategies before their translation to children with LAD.
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PMID:Leukocyte adhesion deficiency in children and Irish setter dogs. 1471 3

Children with the severe phenotype of the genetic immunodeficiency disease leukocyte adhesion deficiency or LAD experience life-threatening bacterial infections because of molecular defects in the leukocyte integrin CD18 molecule and the resultant failure to express the CD11/CD18 adhesion molecules on the leukocyte surface. Hematopoietic stem cell transplantation remains the only definitive therapy for LAD; however, the degree of donor chimerism and particularly the number of CD18(+) donor-derived neutrophils required to reverse the disease phenotype are not known. We performed nonmyeloablative hematopoietic stem cell transplantations from healthy matched littermates in 9 dogs with the canine form of LAD known as CLAD and demonstrate that in the 3 dogs with the lowest level of donor chimerism, less than 500 CD18(+) donor-derived neutrophils/microL in the peripheral blood of the CLAD recipients resulted in reversal of the CLAD disease phenotype. 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.
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PMID:Very low levels of donor CD18+ neutrophils following allogeneic hematopoietic stem cell transplantation reverse the disease phenotype in canine leukocyte adhesion deficiency. 1471 22


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