Partial Purine Nucleoside Phosphorylase Deficiency (original) (raw)
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Purine Nucleoside Phosphorylase Deficiency: A Molecular Model for Selective Loss of T Cell Function1
The Journal of Immunology
Absence of purine nucleoside phosphorylase (NP) is associated with severe T cell immune deficiency and normal B cell function. Patients with this enzyme defect accumulate inosine, guanosine, and their respective deoxycompounds, all of which are substrates for NP. We have evaluated the effect of these four NP substrates on PHA-stimulated lymphocytes and lymphoblastoid cell lines with B and T cell characteristics. Inosine and deoxyinosine had little inhibitory effect on human lymphocytes, whereas guanosine and deoxyguanosine inhibited DNA and protein synthesis in both PHA-stimulated human lymphocytes and hyman lymphoblastoid cells. In all experiments, deoxyguanosine was more toxic than guanosine. Human lymphoblastoid cells with T cell characteristics (T-LCL) were found to be particularly sensitive to the presence of deoxyguanosine. At low µM concentrations 3H-thymidine and 3H-leucine incorporation into the T-LCL was markedly decreased. At a concentration of 10 µM, no cell growth occur...
The American Journal of Medicine, 1979
Immunologic and metabolic abnormalities were studied in a five year old boy with 0.07 per cent of normal erythrocyte purine nucleoside phosphorylase activity. The clinical course is characterized by severe autoimmune hemolytic anemia, a transient neurologic disorder with tremor and ataxia, and minor infectious illnesses. There is severe lymphopenia with decreased absolute numbers of T and B lymphocytes. Mitogen-stimulated blastogenesis is reduced, but response to allogeneic lymphocytes is normal. A monoclonal IgG protein is present. There is hypouricemia, elevated plasma inosine level, hypouricosuria and an increase in the urinary concentration of inosine and guanosine. The pattern of heterozygote distribution in the patient's family is compatible with an autosomal recessive trait in which heierozygotes are identifiable. In addition, the unusual laboratory and clinical manifestations of this patient illustrate the heterogeneity of the clinical syndrome associated with purine nucleoside phosphorylase deficiency.
A rat model of purine nucleoside phosphorylase deficiency
Immunology, 1986
Purine nucleoside phosphorylase (NP; EC 2.4.2.1) deficiency is associated with selective T-cell dysfunction and normal B-cell immunity. In order to create an in vivo model of this immune deficiency, we administered 8-aminoguanosine to rats. This water-soluble nucleoside was rapidly converted by NP to the more potent inhibitor 8-aminoguanine, which has a Ki of 0.19 microM. The accumulation of inosine in plasma showed that administration of 8-aminoguanosine was effectively inhibiting NP activity. The administration of 8-aminoguanosine with deoxyguanosine produced increased levels of dGTP only in thymus cells, and increased levels of GTP in cells from thymus, spleen and lymph node and in red cells. This correlated with assays of deoxyguanosine kinase, which showed significantly higher activity in thymus cells than in cells from spleen and lymph node. The intraperitoneal injection of 8-aminoguanosine alone or with deoxyguanosine for 8 consecutive days caused significant decreases in the...
The Journal of Pediatrics, 1996
Deficiency of the purine salvage pathway enzyme purine nucleoside phosphorylase causes a combined immunodeficiency and neurologic abnormalities and is usually fatal in childhood. We report the first successful transplantation of bone marrow from a sibling with identical class ii human leukocyte antigens in this condition, demonstrating correction of both lymphocyte metabolic and functional abnormalities. (J PEDIATR 1996; 128:373-6)
A canine model of induced purine nucleoside phosphorylase deficiency
Clinical and experimental immunology, 1986
Purine nucleoside phosphorylase (NP EC 2.4.2.1) deficiency in man is associated with selective T cell dysfunction and normal B cell immunity. To create an in-vivo model of this immune deficiency, we administered 8-aminoguanosine to dogs. This water soluble nucleoside was rapidly converted by NP to the more potent product inhibitor 8-aminoguanine, which had a Ki of 0.52 microM. The accumulation of inosine and exogenous deoxyguanosine in plasma provided evidence that administration of 8-aminoguanosine was effectively inhibiting NP activity. Four dogs given 8-aminoguanosine and deoxyguanosine concurrently for 5 consecutive days showed mean reductions in peripheral blood lymphocytes of 65 +/- 9% range (55-75%) over the test period. Granulocytes, red blood cells, and plateletes remained within the normal range. Administration of 8-aminoguanosine to dogs provides a model of NP deficiency that will permit studies of the specific control of lymphopoiesis and in-vivo immune function.
Purine nucleoside modulation of functions of human lymphocytes
Cellular Immunology, 1990
The accumulation of endogenous substrates in patients with adenosine deaminase deficiency or purine nucleoside phosphorylase deficiency is believed to be responsible for the immunodeficiency observed in these patients. To identify the lymphocyte populations that are most susceptible to these substrates, we investigated the effect of their nucleoside analogs on a number of T and B cell functions of human lymphocytes. We found that tubercidin (Tub), 2-chloro 2'deoxyadenosine (2CldA), 2-fluoro adenine arabinoside-5'phosphate (FaraAMP), and 9-0-Darabinosyl guanine (AraGua) inhibited the proliferative responses of human peripheral blood mononuclear cells (PBMC) to polyclonal activators (PHA, OKT3 mab) or to allogeneic PBMC in mixed lymphocyte cultures (MLC). Addition of recombinant IL2 from the beginning of the culture did not alter the inhibition by Tub of the proliferative responses of PBMC. These purine nucleoside analogs also inhibited the proliferative responses of purified human peripheral blood CD4+ and CDS+ T cells to PHA and of purified B cells to SAC. The concentrations of these nucleosides required to achieve a given degree of inhibition of proliferative responses of T lymphocyte subpopulations or B cells was similar, suggesting that these analogs do not exhibit any selectivity for these purified lymphocyte populations. Tub and FaraAMP, respectively, inhibited and enhanced, at the effector phase, both NK cytotoxicity and specific T cell-mediated cytotoxicity. In contrast to these findings, LAK cytotoxicity at the effector phase was not significantly inhibited by Tub, and was not enhanced by FaraAMP. Both analogs inhibited rIL-2-induced proliferative responses of PBMC, but did not affect the generation of LAK cytotoxicity (induction phase) against the K562 targets when added at the beginning of the culture. This suggests that DNA synthesis is not required for LAK cell induction. Both Tub and FaraAMP inhibited immunoglobulin production (IgG and IgM) by PBMC in the PWM-induced system. These results demonstrate that purine nucieoside analogs SignificantIy inhibited a number of functions of human lymphocytes. Although selectivity for T lymphocyte subpopulations and B cells was not observed, a differential effect of Tub and FaraAMP on LAK cytotoxicity versus NK cytotoxicity and specific T cell cytotoxicity was found. o 1990 Academic press, ITIC.
Lymphocyte dysfunction caused by deficiencies in purine metabolism
Immunology Today, 1981
Two inborn errors of purine metabolism have been associated with autosomally inherited human immuno-cl~cienc 7 diseases, A lack of adenosirw deaminase ( ADA) produces severe lymphopenia and a combined immunodeficiency .~yndrome. A d~ciency of purine nucIeoside pho~phoryIase ( PNP) is associated with a selective cellular bnmune deficit. This article discusses the probable biochemical basis for lymphocyte-specifc toxicity in these disordeTs,
Biochemical Genetics, 1980
Purine and pyrimidine metabolism was compared in erythrocytes from three patients from two families with purine nucleoside phosphorylase deficiency and T-cell immunodeficiency, one heterozygote subject for this enzyme deficiency, one patient with a complete deficiency of hypoxanthine-guanine phosphoribosyltransferase, and two normal subjects. The erythrocytes from the heterozygote subject were indistinguishable from the normal erythrocytes. The purine nucleoside phosphorylase deficient erythrocytes had a block in the conversion of inosine to hypoxanthine. The erythrocytes with 0.07%o of normal purine nueleoside phosphorylase activity resembled erythrocytes with hypoxanthine-guanine phosphoribosyltransferase deficiency by having an elevated intracellular concentration of PP-ribose-P, increased synthesis of PP-ribose-P, and an elevated rate of carbon dioxide release from orotic acid during its conversion to UMP. Two hypotheses to account for the associated immunodeficiency--that the enzyme deficiency leads to a block of PP-ribose-P synthesis or inhibition of pyrimidine synthesis--could not be supported by observations in erythrocytes from both enzyme-deficient families.