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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are two ways to find the cause of primary immunodeficiency diseases. One approach is to start with the immune defect and work backwards, using in vitro techniques to define where the primary abnormality lies in the immune response. Immunologists favour this approach for obvious reasons; and it is not without virtue since, for example, it has shown that the defect in most cases of primary hypogammaglobulinaemia is due to a failure of B lymphocyte maturation. The alternative approach is to screen empirically for defects in biochemical pathways in the hope of finding a clue which will eventually lead to the underlying disorder. This is a sensible approach in diseases which are clearly inherited (e.g. X-linked hypogammaglobulinaemia) but is less attractive in a disease such as late onset hypogammaglobulinaemia which is not obviously inherited. In practice, such procedures involve screening the urine for abnormalities in the quality or quantity of excreted compounds. Another way is to screen for abnormalities in organelle integrity by measuring the activity of various enzymes in subcellular fractions. In reality, the clue to the metabolic defect is usually discovered by accident, the prime example in our field being the discovery of adenosine deaminase (ADA) deficiency.
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PMID:Metabolic defects in immunodeficiency diseases. 629 Jan 13

We have studied purine metabolism in mononuclear and polymorphonuclear cells from uraemic patients using microradiochemical enzyme assays and high-pressure liquid chromatography. In mononuclear cell lysates the mean activities of adenosine deaminase (EC 3.5.4.4) and 5'-nucleotidase (EC 3.1.3.5) were significantly diminished. The activities of adenylate kinase (EC 2.7.4.3), purine nucleoside phosphorylase (EC 2.4.2.1), adenine phosphoribosyltransferase (EC 2.4.2.7), and hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) were not significantly different in the two groups. The activities of adenosine deaminase and adenine phosphoribosyltransferase were reduced in the polymorphonuclear cell lysates. No clear differences emerged in the concentration of adenine nucleotides in the mononuclear cells. The significance of these changes, which are less marked than those in erythrocytes, is discussed with reference to the immunodeficiency associated with uraemia.
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PMID:Activities of enzymes involved in purine metabolism and some related adenine nucleotide concentrations of leucocytes in renal failure. 629 37

Phagocytosis and membrane perturbation in mouse macrophages results in an increased superoxide ion production which is in direct proportion to the concomitant increase in adenosine deaminase activity. Since adenosine deaminase activity controls the amount of substrate available to xanthine oxidase, and the latter produces superoxide during turnover of its substrates, it is proposed that the purine salvage pathway is an important source of the superoxide requirement of macrophages. It is further proposed that this may be the basis, at least in part, for the mechanism of the association of immunodeficiency with adenosine deaminase deficiency.
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PMID:Positive correlation between adenosine deaminase activity and superoxide formation during phagocytosis. 630 Feb 72

The association of adenosine deaminase (ADA) deficiency with immunodeficiency disease has emphasized the importance of this purine metabolic enzyme for human lymphocyte growth and function. This report describes the natural occurrence of ADA deficiency in a human histiocytic lymphoma cell line, DHL-9. The minimal ADA activity in DHL-9 extracts, 0.028 nmol/min/mg protein, was less than 50% of the activity in two B-lymphoblastoid cell lines from ADA-deficient patients and was resistant to the potent ADA inhibitor deoxycoformycin. A sensitive radioimmunoassay failed to detect immunoreactive ADA in DHL-9 cells. Moreover, in DHL-9 cells, deoxycoformycin did not augment either the growth-inhibitory effects of adenosine and deoxyadenosine or the accumulation of deoxyadenosine triphosphate from deoxyadenosine. When compared to six other human hematopoietic cell lines, DHL-9 had 5.6-fold-higher levels of adenosylhomocysteinase. Chromosome 20, which bears the structural gene for ADA and adenosylhomocysteinase, was diploid and had a normal Giemsa banding pattern. The parental DHL-9 cell line was used for the selection and cloning of secondary mutants deficient in deoxycytidine kinase and adenosine kinase.
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PMID:Characterization of an adenosine deaminase-deficient human histiocytic lymphoma cell line (DHL-9) and selection of mutants deficient in adenosir kinase and deoxycytidine kinase. 630 63

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 association of a genetic deficiency of adenosine deaminase (ADA) with immunodeficiency disease has emphasized the importance of deoxyadenosine and adenosine metabolism for human lymphocyte function. However, information concerning the endogenous production and metabolism of deoxyadenosine and adenosine in normally growing human T and B lymphoblasts is lacking. In the present experiments, we used a diverse series of cell lines deficient in individual enzymes of purine metabolism to quantitate the de novo formation of deoxyadenosine and adenosine in human T lymphoblasts (CEM), B lymphoblasts (WI-L2), and histiocytic lymphoma cells (DHL-9). The B lymphoblasts and histiocytic lymphoma cells generated deoxyadenosine at a rate of 60 to 80 pmol/hr/10(7) cells. This value was several fold greater than the rate of production of deoxyadenosine by T cells (6 to 7 pmol/hr/10(7) cells). Deoxyadenosine synthesis required ribonucleotide reductase activity, and was maximal during the S-phase of the cell cycle. The T and B lymphoblasts formed relatively similar amounts of adenosine (870 to 1620 pmol/hr/10(7) cells) throughout the cell cycle. In ADA-deficient cells, a major fraction of the deoxyadenosine synthesized de novo was excreted into the extracellular space. These results establish that the endogenous synthesis and metabolism of deoxyadenosine (but not adenosine) is distinctly different in T and B lymphoblasts.
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PMID:Differential production of deoxyadenosine by human T and B lymphoblasts. 635 3

The discovery of the causal association of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency with some forms of primary immunodeficiency disease had led to new approaches to therapy, such as enzyme replacement. In ADA deficiency, bone marrow transplantation remains the primary method of choice. If no suitable bone marrow donor is available, enzyme replacement with irradiated erythrocyte transfusions should be considered. The latter therapy may be sustained by treatment with thymic factors. In ADA deficiency, bone marrow transplantation and, in about 50% of the cases, also enzyme replacement, may result in clinical and neurological improvement with concurrent (partial) restoration of immune function and (partial) disappearance of the metabolic abnormalities present before treatment. In PNP deficiency, enzyme replacement has been evaluated carefully in only two patients. The results disclose profound changes in the purine excretion patterns after each transfusion, and a slow but partial restoration of in vitro T cell function. Treatment of ADA and PNP deficiency with continued enzyme replacement by erythrocyte transfusions has certain risks which hopefully can be overcome in the near future by loading the patient's own blood cells with the missing enzyme.
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PMID:Therapy in adenosine deaminase and purine nucleoside phosphorylase deficient patients. 640 80

Low ATP/ADP ratios have been reported consistently for nucleotide levels of mononuclear cells separated from peripheral blood by conventional techniques. We have established that these low values (mean 2.3:1) were not due to cell damage or poor viability, but resulted from heavy platelet contamination, which is unavoidable when heparinized blood is used. The results reflect the low ATP/ADP ratios (mean 1.6:1) characteristic of platelets. Platelet-free extracts from defibrinated blood had very high ATP/ADP ratios (mean 17.4:1). The initial finding of detectable amounts of deoxy-ATP and deoxy-GTP in mononuclear cells from children with two distinct inherited immunodeficiency disorders [adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency respectively] many have been due to contamination by nucleated erythrocytes as well as platelets in non-defibrinated preparations. Defibrination before nucleotide extraction of mononuclear cells from a patient with T-cell leukaemic/lymphoma treated with the ADA inhibitor deoxycoformycin enabled the demonstration of grossly raised deoxy-ATP levels relative to deoxy-ADP levels (ratio 16.1:1), associated with severe ATP depletion. This reciprocal relationship between ATP and dATP was found by us previously in the erythrocytes in inherited ADA deficiency. These findings underline the importance of extracts uncontaminated by platelets, or nucleated erythrocytes, in the evaluation of lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes.
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PMID:Importance of platelet-free preparations for evaluating lymphocyte nucleotide levels in inherited or acquired immunodeficiency syndromes. 641 55

Enzyme inhibitors used to simulate the inherited immunodeficiency diseases, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency, have been assessed in cultured human lymphocytes. Only 2'-deoxycoformycin (dCF) completely inhibited ADA in T and B cells at concentrations in excess of 5 microM. Erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and 8-amino guanosine (8-NH2GR) did not inhibit ADA or PNP completely at any concentration. Detailed metabolic experiments comparing viability and deoxynucleotide accumulation showed that B cell lines of malignant origin also accumulated high levels of dATP from 2'-deoxyadenosine (dAR), and dGTP from 2'-deoxyguanosine (dGR) as effectively as T cells--even without inhibitors, however, dAR reduced cell viability only when ADA was inhibited by dCF, whilst dGR was equally toxic with or without inhibitor, even to a line which accumulated no dGTP. These experiments indicate that cultured lymphocytes, using either EHNA or 8-NH2GR as enzyme inhibitor, are not valid models of the toxicity to the immune system in inherited ADA or PNP deficiency. They demonstrate that the ability to accumulate high levels of dATP or dGTP is not exclusive to T cells and that the in vitro toxicity of dAR or dGR could relate to the use of excess substrate and/or accumulation in different nucleotide, not deoxynucleotide pools.
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PMID:B cells as well as T cells form deoxynucleotides from either deoxyadenosine or deoxyguanosine. 642 86

We investigated adenosine deaminase (ADA) deficient severe-combined immunodeficiency (SCID) in an 8-month-old child with ADA deficient mother. The ADA deficiency in the child was unusual in that the thymic histology was normal. In addition, the thymocytes formed E-rosettes with sheep erythrocytes and were stimulated by T-cell mitogens. ADA activity could not be detected in the child's thymocytes. Studies on the family indicated that the father had about one-half of the normal erythrocyte ADA activity. All the family members with detectable ADA activity appeared to have, according to starch gel electrophoresis of erythrocyte lysates, the common ADA-1 phenotype; however, rigorous identification of phenotype was not possible in this study. The mother had less than 1% of normal ADA activity in both erythrocyte and lymphocyte extracts, but her whole peripheral blood lymphocytes demonstrated about 6% of normal activity. Normal concentrations of ATP and small amounts of dATP were found in the mother's erythrocytes. Deoxyadenosine excretion in her urine was elevated and approximately 5-10% of that excreted by individuals with ADA deficient SCID. These studies suggest that low amounts of ADA activity in erythrocytes and blood lymphocytes of certain individuals may be compatible with good immune function and longevity.
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PMID:Severe combined immunodeficiency in a child with a healthy adenosine deaminase deficient mother. 660 96


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