Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.5.4.4 (adenosine deaminase)
5,136 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autopsy material and clinical information were analyzed in 25 cases of untreated or unsuccessfully treated severe combined immunodeficiency disease and one case successfully treated by bone marrow grafting. Two cases were adenosine deaminase deficient and one was nucleoside phosphorylase deficient. The histological appearance of the thymus fell into four clearly recognizable patterns: simple dysplasia, dysplasia with corticomedullary differentiation, dysplasia with pseudoglandular appearance, and atrophic pattern. Three cases lacked lymph nodes and belonged to the category of thymic dysplasia with pseudoglandular appearance. From the data, the following conclusions can be made: (i) The thymic atrophic pattern is a phase in a dynamic process of which the end result is simple dysplasia or dysplasia with corticomedullary differentiation. (ii) The pseudoglandular pattern represents a disease process of early intrauterine onset. (iii) At least a proportion of the cases represent a T-cell defect rather than a lymphoid stem-cell defect. (iv) The lymphoid germinal centers are not the source of plasma cells. (v) The graft-versus-host reaction probably causes lymphoid cells depletion in lymph nodes and spleen.
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PMID:Severe combined immunodeficiency disease: a pathological analysis of 26 cases. 619 60

In order to determine the molecular basis of adenosine deaminase (ADA) deficiency in cells derived from patients with severe combined immunodeficiency (SCID) disease, we used a human ADA cDNA clone (1) to analyse the organization and transcription of the ADA gene in both normal and ADA-SCID cells. In five lymphoblastoid ADA-SCID cell lines we could detect no deletions or rearrangements in the ADA gene and its flanking sequences. Furthermore, synthesis and processing of ADA mRNA appeared to be normal in the ADA-SCID cells, and ADA-specific mRNA from two ADA-SCID cells could be translated in vitro into a protein with the molecular weight of normal ADA; this protein, however, could hardly be precipitated with an ADA antiserum. The results indicate that in these two ADA-SCID cell lines, the lack of ADA activity is not due to transcriptional or translational defects, but to subtle changes in the configuration of the protein affecting both its enzymatic and immunological characteristics.
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PMID:Adenosine deaminase (ADA) deficiency in cells derived from humans with severe combined immunodeficiency is due to an aberration of the ADA protein. 619 31

A child diagnosed at birth as deficient in red blood cell adenosine deaminase (ADA) but with substantial residual lymphocyte ADA has been evaluated for two and one-half years. The only immunologic abnormality observed was hypogammaglobulinemia during the fifth month of life. This was unexpected because children with total ADA deficiency either have severe combined immunodeficiency or selectively greater impairment of cellular than humoral immunity. The absence of severe combined immunodeficiency in this child was associated with normal lymphocyte content of ATP, dATP, and cyclic 3'5'-adenosine monophosphate, potentially toxic metabolites which are elevated in ADA-deficient immunodeficient children.
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PMID:Adenosine deaminase deficiency without immunodeficiency: clinical and metabolic studies. 625 20

Neutrophils and macrophages generate superoxide anion during the respiratory burst in response to various stimuli, including microorganisms. It has recently been proposed that an important source of superoxide anion during the respiratory burst that stimulates murine macrophages is the sequential metabolism of adenosine via adenosine deaminase and xanthine oxidase to uric acid. Thus, the immunodeficiency state associated with adenosine deaminase deficiency may be caused at least in part by a defect in superoxide anion generation. The ability to generate superoxide anion of stimulated neutrophils isolated from three children with adenosine deaminase deficiency and associated severe combined immunodeficiency was tested. Neutrophils from all three patients were able to generate superoxide anion. One of these generated 19.1 nmol cytochrome c reduced/10(6) cells (normals = 5.3-33.0, mean 18.4 +/- 7.1) while the other two generated low normal levels. Neutrophils from all three children also generated more superoxide anion after addition of exogenous adenosine deaminase. Thus, no evidence to support a role for cellular adenosine deaminase in the release of superoxide anion by stimulated neutrophils was found. Although neutrophils from patients deficient in adenosine deaminase appear to have no inherent defect in the generation of superoxide anion, the abnormally high concentrations of adenosine found in the plasma of these patients could, in vivo, secondarily, inhibit superoxide anion release.
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PMID:Adenosine deaminase is not required for the generation of superoxide anion. 632 Oct 74

The suppressive effects of ATP on murine T-cell functions were studied. The suppressive effects of ATP as well as adenosine on the DNA synthesis of spleen cells are due to the presence of mature T-cells, because ATP has no suppressive effect on athymic nu/nu spleen cells. Further characterization of the cells which are responsible for ATP-mediated suppression of DNA synthesis revealed that the cells are nylon wool-adherent T-cells and PHA-reactive T-cells. In addition, the suppressive effects of ATP on both spontaneous and mitogen-induced proliferative responses are stronger than that of adenosine, and T-cells are more sensitive to ATP than B-cells. The observation that both ATP and adenosine have unique effects on T-cells compared to B-cells may contribute toward explaining why patients with severe combined immunodeficiency (SCID) associated with adenosine deaminase (ADA) deficiency have greater T-cell than B-cell abnormalities.
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PMID:Adenosine 5'-triphosphate (ATP)-mediated stimulation and suppression of DNA synthesis in lymphoid cells. II. Suppressive effect of ATP on murine T-cell functions. 636 11

The immunologic work-up of eight infants with the clinical diagnosis of severe combined immunodeficiency (SCID) was performed with special emphasis on natural killer (NK) cell function and ontogeny. Contrary to previous reports, our study shows that not all SCID patients lack NK activity; some may even express very high NK- and antibody-dependent cellular cytotoxicity (ADCC). The present group of eight SCID infants was homogeneous with respect to normal levels of the purine metabolism enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP). They all had low serum Ig levels and were defective for specific antibody formation against BSA and diphtheria toxin (DiT). None of the infants' peripheral blood mononuclear cells (PBMC) proliferated significantly upon in vitro stimulation with PHA, concanavalin A (Con A), pokeweed mitogen (PWM), and irradiated allogeneic lymphocytes. Seven of eight patients, however, responded significantly to mitogenic factors present in a lectin-free interleukin 2 (IL 2) preparation, and two exhibited a positive costimulation as well with simultaneous exposure to IL 2 + Con A. The lymphocyte marker analysis revealed high percentages of OKT10+ cells in seven of eight infants, whereas peripheral T cells (OKT3+) with suppressor/killer (OKT8+) or helper/inducer (OKT4+) phenotypes were abnormally low in all infants with one exception. The PBMC of two patients formed low to normal percentages of E rosettes but expressed no B cell markers (B-/SCID). The six other infants had high percentages of B cells (B+/SCID) but lacked E rosette-forming cells. High NK and ADCC activity was found in the two B-/SCID patients. The B+/SCID infants either totally lacked NK and ADCC function (four of six) or expressed low to normal NK activity together with some T cell markers as revealed by monoclonal antibody staining but not by E rosette formation (two of six). From the data presented, an ontogenic model is proposed that assumes the status of an independent cell lineage in between T cells and monocytes for human NK cells, or that places these cells in close proximity to early differentiation steps of the T cell lineage. In any case, NK cell function clearly constitutes an additional parameter of heterogeneity in the immunologic analysis of SCID.
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PMID:NK cell function in severe combined immunodeficiency (SCID): evidence of a common T and NK cell defect in some but not all SCID patients. 641 62

Pokeweed mitogen-induced B lymphocyte differentiation in vitro into antibody secreting plaque-forming cells (PFC) was investigated in nine patients with severe combined immunodeficiency having variable proportions of circulating B lymphocytes. When cultured by themselves, the peripheral blood mononuclear cells did not respond to stimulation with pokeweed mitogen in any patient. In the presence of irradiated allogeneic T cells as helpers, however, PFC responses were elicited in lymphocyte cultures from peripheral blood and/or bone marrow in some patients. In one of these patients, results of allogeneic co-culture experiments were suggestive of genetically restricted suppressor cells. In a single patient with deficiency of the enzyme adenosine deaminase, PFC were generated in bone marrow lymphocyte cultures only when they were supplemented with exogenous adenosine deaminase and allogeneic helper cells. A parallel study of T lymphocyte differentiation in vitro performed in fractionated bone marrow cells was suggestive of arrested differentiation at different steps along the differentiation pathway. In two patients with evidence of functional B cell precursors, deficiencies of helper T cell function could be attributed to differentiation defects at the level of the stem cells in one and the thymus in the other. The findings reported here further substantiate the heterogeneity of the severe combined immunodeficiency disease syndromes.
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PMID:Heterogeneity of b lymphocyte differentiation in severe combined immunodeficiency disease. 644 66

Deficiency of adenosine deaminase (ADA) in lymphocytes seems to be responsible for severe combined immunodeficiency (SCID), a syndrome in early infancy untreated resulting in death. The highest amounts of ADA activity are found in lymphoid tissues. Considerable enzyme deficiency is associated with an inhibition of proliferation and differentiation, especially of the T lymphocytes, and gives rise primarily to disordered cellular immunity. The molecular mechanisms of the relationship between enzyme deficiency and immune dysfunction are widely unknown. Several possibilities are discussed. Deoxyadenosine and its nucleotides seem to be the toxic agents. The enzyme deficiency is thought to result from a mutation at the structural locus of ADA inherited in an autosomal recessive mode. In addition to transplantation of bone marrow, fetal liver, or thymus the "enzyme replacement" has been suggested for therapy of SCID in ADA deficiency, i.e. transfusion of irradiated erythrocytes with normal ADA activity.
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PMID:[Adenosine deaminase activity and immune dysfunction (author's transl)]. 645 54

In most instances, marked deficiency of the purine catabolic enzyme adenosine deaminase results in lymphopenia and severe combined immunodeficiency disease. Over a 2-yr period, we studied a white male child with markedly deficient erythrocyte and lymphocyte adenosine deaminase activity and normal immune function. We have documented that (a) adenosine deaminase activity and immunoreactive protein are undetectable in erythrocytes, 0.9% of normal in lymphocytes, 4% in cultured lymphoblasts, and 14% in skin fibroblasts; (b) plasma adenosine and deoxyadenosine levels are undetectable and deoxy ATP levels are only slightly elevated in lymphocytes and in erythrocytes; (c) no defect in deoxyadenosine metabolism is present in the proband's cultured lymphoblasts; (d) lymphoblast adenosine deaminase has normal enzyme kinetics, absolute specific activity, S20,w, pH optimum, and heat stability; and (e) the proband's adenosine deaminase exhibits a normal apparent subunit molecular weight but an abnormal isoelectric pH. In contrast to the three other adenosine deaminase-deficient healthy subjects who have been described, the proband is unique in demonstrating an acidic, heat-stable protein mutation of the enzyme that is associated with less than 1% lymphocyte adenosine deaminase activity. Residual adenosine deaminase activity in tissues other than lymphocytes may suffice to metabolize the otherwise lymphotoxic enzyme substrate(s) and account for the preservation of normal immune function.
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PMID:Adenosine deaminase deficiency with normal immune function. An acidic enzyme mutation. 660 77

The prenatal diagnosis of severe combined immunodeficiency (SCID) was made in three fetuses by staining fetal blood obtained at fetoscopy with a panel of monoclonal antibodies. There were less than 100 T cells/mm3 of fetal blood in these three cases compared to 2,500/mm3 in 14 immunologically normal fetuses. Cells bearing the cortical thymocyte antigen (NA1/34) were not detected in any of the normal or affected fetal blood samples. Two of the affected fetuses were also homozygous for a deficiency of adenosine deaminase (ADA) with undetectable levels of red cell ADA. All three affected fetuses were aborted and postmortem tissue was obtained in two cases. In both of these cases the thymus was markedly hypoplastic and contained no lymphoid cells. One of these fetuses was homozygous for ADA deficiency and the virtual absence of T cells or thymocytes during the second trimester of pregnancy indicates that placental access to the maternal circulation does not prevent damage to the T lineage stem cells in this disease. Prenatal diagnosis of SCID has previously only been possible in patients with a defined metabolic defect such as ADA deficiency, but these studies indicate that prenatal diagnosis now may be offered for most at risk pregnancies.
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PMID:Prenatal diagnosis of three cases of severe combined immunodeficiency: severe T cell deficiency during the first half of gestation in fetuses with adenosine deaminase deficiency. 661 May 9


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