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)

A number of infants with an autosomal recessive form of combined immunodeficiency disease also lack adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in their erythrocytes. Other tissues from these infants contain only a few percent of the adenosine-deaminating activity present in corresponding normal tissue. The residual adenosine-deaminating activity in extracts from the spleen of a combined immunodeficient, adenosine deaminase-deficient patient was compared with adenosine deaminase from normal spleen. Affinity and immunoadsorbant column chromatography revealed distinct differences between the adenosine-deaminating activity in the patient's spleen and adenosine deaminase from normal spleen. The point of maximum activity and general configuration of the pH optimum curves were also different. erythro-9-(2-Hydroxyl-3-nonyl)adenine, a potent inhibitor of adenosine deaminase from normal spleen, had relatively little effect on the activity from the patient's spleen. In contrast, adenine was a better inhibitor of the activity in the patient's spleen than it was of the enzyme from normal tissue. An adenosine-deaminating activity with the same characteristics and specific activity as that in the patient's spleen was also isolated from normal spleen. These results suggest that the adenosine-deaminating activity in the spleen of this patient is not due to a mutant form of adenosine deaminase.
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PMID:Characterization of the residual adenosine deaminating activity in the spleen of a patient with combined immunodeficiency disease and adenosine deaminase deficiency. 2 16

The inherited deficiency of adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4) activity in humans is associated with an immunodeficiency. Some of the immunodeficient and enzyme-deficient patients respond immunologically to periodic infusions of irradiated erythrocytes containing adenosine deaminase. It has been previously reported that erythrocytes and lymphocytes from immunodeficient ane enzyme-deficient children contained increased concentrations of ATP, and in the one child studied after erythrocyte infusion therapy, the intracellular level of ATP diminished. Using high-pressure liquid chromatography that resolves ATP and 2'-dATP, we have observed greater than 50-fold elevations of dATP in the erythrocytes of immunodeficient, adenosine deaminase-deficient patients but not in the erythrocytes of an immunocompetent adenosine deaminase-deficient patient. The erythrocyte dATP in two unrelated adenosine deaminase-deficient, immunodeficient patients disappeared after infusion of normal erythrocytes. We propose that deoxyadenosine, a substrate of adenosine deaminase, is the potentially toxic substrate in adenosine deaminase deficiency, and that the mediator of the toxic effect is dATP, a recognized potent inhibitor of ribonucleotide reductase.
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PMID:Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. 27 65

Deoxyadenosine at low concentrations and in the presence of an inhibitor of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) is markedly toxic to lymphoblast cell lines of T cell origin but does not impair growth of B cell lines. Deoxyguanosine is also more toxic for T lymphoblasts. In the presence of deoxyadenosine or deoxyguanosine, elevation of the corresponding deoxyribonucleoside triphosphate (dATP or dGTP) occurs in T cell, but not in B cell, lines. The addition of deoxycytidine or dipyridamole results in lower dATP and dGTP levels and prevents deoxyribonucleoside toxicity. These findings provide a molecular basis for the immunodeficiency observed in individuals with several inborn errors of purine metabolism.
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PMID:Purinogenic immunodeficiency diseases: selective toxicity of deoxyribonucleosides for T cells. 31 Oct 4

We studied a 15-month-old girl who had normal T-cell and B-cell immunity at birth, after which a gradual decrease in T-cell immunity developed. This selective cellular immunodeficiency was inherited as an autosomal recessive trait: two older sisters had the same immunodeficiency. Adenosine deaminase activity was present in erythrocytes and lymphocytes of the patient, parents and a healthy brother. Purine nucleoside phosphorylase activity was not found in the patient's erythrocytes and lymphocytes (the parents and brother had intermediate values, indicating that the enzyme deficiency too was inherited as an autosomal recessive trait). Analysis of serum and urine from the patient and of serum from her two deceased sisters showed high levels of inosine and guanosine in addition to hypouricemia and hypouricosuria. The bone marrow was megaloblastic, and the blood hypochromic microcytic. The patient had spastic tetraparesis. Intoxication of the T lymphocytes after birth by metabolic products may explain the progressive cellular immunodeficiency.
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PMID:Purine nucleoside phosphorylase deficiency associated with selective cellular immunodeficiency. 40 73

Adenosine deaminase (ADA) could be quantitated and the isozyme pattern characterized in cultured amniotic fluid cells. In 20 amniotic fluid cell cultures the mean specific activity was 14.3 U/g protein +/- 6.7 (SD) and compared favorably with values of 14.6 U/g protein +/- 6.8 (SD) observed in 26 cultures of skin fibroblasts. In cultures of skin fibroblasts established from two obligate heterozygotes for ADA deficiency, the specific activity of ADA was 7.0 and 7.7 U/g protein. The ADA isozyme pattern that existed in cultures of amniotic fluid cells was the same as that observed in cultured skin fibroblasts. This identification of the same apparent enzyme may permit the prenatal diagnosis of that form of combined immunodeficiency disease caused by ADA deficiency. Residual enzyme activity of less than 1% and 10% of the mean of normal fibroblasts could be measured in cultured fibroblasts from two unrelated children with ADA deficiency and combined immunodeficiency disease. The tissue-specific enzyme from cultured skin fibroblasts from the child with 10% residual activity had a faster electrophoretic mobility and greater heat stability than normal ADA. This enzymatic evidence indicates that at least two mutant alleles exist at the locus for ADA which predispose to combined immunodeficiency disease when present in the homozygous state.
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PMID:Heterogeneity for adenosine deaminase deficiency: Expression of the enzyme in cultured skin fibroblasts and amniotic fluid cells. 115 49

Adenosine deaminase (ADA) deficiency is one the causes of severe combined immunodeficiency syndrome. Treatment was, until now, based on bone marrow transplantation. HLA identical bone marrow transplantation yields excellent results while those of HLA haploidentical bone marrow transplantation are not so good. A new therapeutic approach was developed recently, consisting of the intramuscular infusion of ADA enzyme covalently linked to polyethylene glycol (PEG-ADA). We report the results of this treatment in a 14 month-old child presenting with a partial form of ADA deficiency revealed by an opportunistic infection. This treatment corrected the immunodeficiency and the biochemical abnormalities as well. PEG-ADA infusions were well tolerated. The onset of an immunization against the ADA enzyme led to a drop in immunologic functions, which could be partially overcome by more frequent (biweekly) administration of the product. After a 18 month-follow-up the child is doing well, living normally at home. PEG-ADA represents a possible alternative for children presenting with ADA deficiency without any available HLA identical donor.
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PMID:[Treatment of adenosine deaminase deficiency with adenosine deaminase combined with polyethylene glycol]. 149 22

Adenosine deaminase, which is essential for lymphoid differentiation and function, has previously been considered to be a cytosolic enzyme. In this report we demonstrate that it can be found associated with the plasma membrane of lymphocytes. By means of immunological techniques using both light and electron microscopy, adenosine deaminase was localized on the external side of the plasma membrane of normal lymphocytes and monocytes. Since the enzyme expression differed depending on the type of cell examined, new hypotheses about the mechanisms involving purine metabolism in immune dysfunctions or immunodeficiency syndromes may be considered.
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PMID:Presence of adenosine deaminase on the surface of mononuclear blood cells: immunochemical localization using light and electron microscopy. 185 51

Four 2-amino-6-halo- and four 6-halo-2',3'-dideoxypurine ribofuranosides (ddPs) were synthesized and tested for in vitro activity to suppress the infectivity, cytopathic effect, Gag protein expression, and DNA synthesis of human immunodeficiency virus (HIV). The comparative order of in vitro anti-HIV activity of the eight 6-halo-ddPs was as follows: 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro greater than 2-amino-6-bromo greater than 2-amino-6-iodo, 6-chloro greater than 6-bromo greater than 6-iodo. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddPs showed a potent activity against HIV comparable to that of 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG) and completely blocked the infectivity of HIV without affecting the growth of target cells. The lipophilicity order was as follows: 2-amino-6-iodo greater than 2-amino-6-bromo greater than 2-amino-6-chloro greater than 2-amino-6-fluoro much greater than ddG greater than ddI. All eight 6-halo-ddPs were substrates for adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4). The relative rates of hydrolysis by ADA were as follows: ddA, 2-amino-6-fluoro much greater than 2-amino-6-chloro, 2-amino-6-bromo greater than 2-amino-6-iodo. Taken together, these compounds may represent an additional class of lipophilic prodrugs for ddI and ddG and may also provide a strategy for endowing therapeutic purine nucleosides with desirable lipophilicity.
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PMID:Lipophilic halogenated congeners of 2',3'-dideoxypurine nucleosides active against human immunodeficiency virus in vitro. 225 Dec 84

Enzyme activities were studied in peripheral blood lymphocytes from patients infected with, or at risk for, infection with human immunodeficiency virus (HIV). No significant differences were observed in the HIV-infected and HIV-seronegative high-risk patients with regard to enzyme activities of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) and purine nucleoside phosphorylase (EC 2.4.2.1) in peripheral blood. Adenosine deaminase (EC 3.5.4.4) was significantly (P less than 0.02) depressed in asymptomatic HIV-seropositive patients and HIV-seronegative patients at high risk of HIV infection as compared with a healthy HIV-seronegative population. Adenosine kinase (AK, EC 2.7.1.20) was significantly increased in the asymptomatic seropositive (P less than 0.02) and also in the HIV-seronegative high-risk groups (P = 0.01) compared with the normal controls. AK activity was significantly lower in subjects with AIDS than in the asymptomatic (P less than 0.002) and high-risk groups (P less than 0.01). Taken together, these results indicate that adenosine deaminase and AK activities are influenced by the health of the patient, and that measurement of AK activity may prove useful in monitoring the clinical progress of patients with HIV infection.
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PMID:Depressed activities of purine enzymes in lymphocytes of patients infected with human immunodeficiency virus. 254 31

Deficiencies of two enzymes that catalyze sequential reactions in the purine catabolic pathway have been causally associated with immunodeficiency states. Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency disease, while purine nucleoside phosphorylase (PNP) deficiency results in an isolated T-cell defect. Recent work in this area has provided major new insights into the molecular pathology of these syndromes. Deoxyadenosine and deoxyguanosine, substrates that accumulate in ADA and deoxyguanosine, substrates that accumulate in ADA and PNP deficiency, respectively, appear to be selectively phosphorylated by lymphoid cells to the corresponding deoxynucleoside triphosphate, resulting in inhibition of DNA synthesis in these cells. Both deoxynucleosides are far more toxic to cultured T lymphoblasts than to B lymphoblasts. Adenosine and deoxyadenosine may have additional lymphotoxic effects mediated by inhibition of essential methylation reactions. These observations help to explain the immunologic manifestations of ADA and PNP deficiency. Perhaps more important, they lay the foundation for the use of deoxynucleosides or enzyme inhibitors, or both, as selective immunosuppressive and chemotherapeutic agents.
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PMID:Purinogenic immunodeficiency diseases: clinical features and molecular mechanisms. 624 48


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