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Lymphospecific Toxicity in Adenosine Deaminase Deficiency and Purine

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Lymphospecific Toxicity in Adenosine Deaminase Deficiency and Purine Proc. Nati. Acad. Sci. USA Vol. 74, No. 12, pp. 5677-5681, December 1977 Immunology Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: Possible role of nucleoside kinase(s) (immunodeficiency/lymphocyte/purine deoxyribonucleoside kinase/purine deoxyribonucleotides) DENNIS A. CARSON*, JONATHAN KAYE*, AND J. E. SEEGMILLERt *Division of Rheumatology, Department of Clinical Research, Scripps Clinic and Research Foundation, La Jolla, California 92037; and t Department of Medicine, University of California, San Diego, La Jolla, California 92037 Contributed by J. Edwin Seegmiller, September 26, 1977 ABSTRACT Inherited deficiencies of the enzymes adeno- deaminase deficiency by enzyme replacement in the form of sine deaminase (adenosine aminohydrolase; EC 3.5.4.4) and purine nucleoside phosphorylase (purine-nucleoside:ortho- erythrocyte transfusions (4). phosphate ribosyltransferase; EC 2.4.2.1) preferentially interfere Three biochemical mechanisms have been proposed to ex- with lymphocyte development while sparing most other organ plain the association of deaminase deficiency with immuno- systems. Previous experiments have shown that through the deficiency disease, i.e., adenosine-induced pyrimidine star- action of specific kinases, nucleosides can be "trapped" intra- vation (5), hypoxanthine deficiency (6), and adenosine-me- cellularly in the form of 5'-phosphates. We therefore measured diated elevations in cyclic AMP concentrations (7). In the ab- the ability of newborn human tissues to phosphorylate adeno- sine and deoxyadenosine, the substrate of adenosine deaminase, sence of further information, these hypotheses do not explain and also inosine, deoxyinosine, guanosine, and deoxyguanosine, the preferential impairment of lymphoid development seen the substrates of purine nucleoside phosphorylase. Substantial in both phosphorylase and deaminase deficiency. In the present activities of adenosine kinase were found in all tissues studied, studies, we suggest that lymphospecific toxicity in deaminase while guanosine and inosine kinases were detected in none. and phosphorylase deficiency may result from the selective However, the ability to phosphorylate deoxyadenosine, deoxy- accumulation in inosine, and deoxyguanosine was largely confined to lympho- lymphoid tissues, particularly the thymus, of cytes. Adenosine deaminase, but not purine nucleoside phos- toxic deoxyribonucleotides, mediated by nucleoside phorylase, showed a similar lymphoid predominance. Other kinase(s). experiments showed that deoxyadenosine, deoxyinosine, and deoxyguanosine were toxic to human lymphoid cells. The tox- icity of deoxyadenosine was reversed by the addition of de- MATERIALS AND METHODS oxycytidine, but not uridine, to the culture medium. Based upon Tissue Extracts. Newborn human tissues obtained at these and other experiments, we propose that in adenosine autopsy deaminase and purine nucleoside phosphorylase deficiency, within 24 hr of death were frozen at -20°. Extracts were pre- toxic deoxyribonucleosides produced by many tissues are se- pared by mincing the specimens in 10 mM Tris buffer (pH 7.4), lectively trapped in lymphocytes by phosphorylating en- followed by five cycles of freeze-thawing, and ultracentrifu- zyme(s). gation of the particulate material. Peripheral blood lymphocytes and granulocytes were isolated During the past 5 years, Giblett and her colleagues have dem- by dextran sedimentation of heparinized whole blood from an onstrated an association between severe deficiencies of either adult volunteer, followed by centrifugation through Ficoll- adenosine deaminase (adenosine aminohydrolase; EC 3.5.4.4), Hypaque (8). Red cells were lysed with Tris-buffered ammo- or purine nucleoside phosphorylase (purine-nucleoside:ortho- nium chloride and the cells were washed and frozen (9). phosphate ribosyltransferase; EC 2.4.2.1) and inherited forms The protein content of all tissue extracts was determined by of human immunodeficiency disease (1, 2). Although the Lowry's method, with bovine serum albumin as a standard clinical pictures overlap, children with adenosine deaminase (10). deficiency usually suffer from a combined immunodeficiency Enzyme Assays. Kinase activities in cell extracts and column syndrome, with impairment of T cell development and in most fractions were determined by a modification of the method of cases of B cell function as well, while those with purine nucle- Ives et al. (11). For the measurement of deoxyguanosine, gua- oside phosphorylase deficiency have primarily a deficit in T nosine, deoxyinosine, and inosine kinases, the final concentra- cell development and the associated cellular immune functions. tions of the reactants were: 50mM Tris (final pH 7.4), 10 mM Both diseases are accompanied by severe lymphopenia. Al- ATP, 10 mM MgCI2, 15 mM NaF, 1 mg of protein per ml, and though enzyme is virtually absent from all tissues examined, 0.4-2 ,uCi of substrate at a concentration of 300 ,M in a total apparently only the growth and development of the lymphoid volume of 100 X. Adenosine and deoxyadenosine kinases were system is severely retarded (3). It is therefore likely that the similarly measured, except that the ATP and magnesium immune defect in deaminase and phosphorylase deficiency is concentrations were 5 and 2.5 mM, respectively. In addition, not due to a generalized disorder of growth, but rather to a to each sample was added the deaminase inhibitor erythro- primary lymphocyte abnormality and/or circulating toxins that 9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA) to a final are specifically lymphocytoxic. The latter concept is in accord concentration of 5 ,M. with the reversal of the immunodeficient state accompanying The reactions were initiated by the addition of labeled sub- strate. After 30 min at 370 in a shaking water bath, the samples The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked Abbreviations: deaminase, adenosine deaminase; phosphorylase, purine "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate nucleoside phosphorylase; EHNA, erythro-9-(2 hydroxy-3-nonyl)- this fact. adenine hydrochloride. 5677 Downloaded by guest on October 2, 2021 5678 Immunology: Carson et al. Proc. Natl. Acad. Sci. USA 74 (1977) Table 1. Enzyme activities in human tissues Purine Adenosine Deoxyadenosine Deoxyguanosine Deoxyinosine Adenosine nucleoside kinase kinase kinase kinase deaminase phosphorylase I II I II I II I II II II Thymus 0.79 0.86 1.35 0.78 1.92 1.39 0.34 0.31 982.8 23.3 Spleen NA 0.53 NA 0.20 NA 0.33 NA 0.07 12.4 54.0 Brain NA 1.01 NA 0.14 NA 0.16 NA 0.05 5.0 10.3 Kidney NA 1.15 NA 0.07 NA 0.08 NA 0.10 1.8 100.0 Liver 0.81 2.26 0.12 0.07 0.04 0.07 0.05 0.04 1.1 36.2 Lung 1.32 0.81 0.11 0.06 0.03 0.08 0.03 0.02 0.8 38.0 Small intestine 0.41 0.52 0.13 0.08 0.03 0.11 0.09 0.07 14.2 63.9 Heart 0.48 0.51 0.13 0.08 0.03 0.11 0.07 0.06 2.1 32.2 Peripheral lymphocytes 1.00 0.32 0.21 0.09 20.7 114.7 Peripheral granulocytes 0.83 0.05 <0.02 0.03 11.9 121.4 Human tissues were obtained from two babies (I and II) who died during parturition, while peripheral lymphocytes and granulocytes were isolated from the blood of a normal adult. Activities are expressed as nmol of product per min/mg of protein at a substrate concentration of 300 PM. NA, not available for study. were boiled for 2 min and insoluble material was centrifuged Reagents. [8-14C[Adenosine and [8- 4C[deoxyadenosine at 4°. Control experiments with [14C]inosine monophosphate were purchased from New England Nuclear (Boston, MA) and showed no nucleotide breakdown under these conditions. used to synthesize inosine and deoxyinosine by treatment with Nucleotides were separated from the nucleosides and bases calf deaminase (Calbiochem, San Diego, CA). [8-14C]Guanosine by chromatography on PEI-cellulose thin-layer plates (E. was also obtained from New England Nuclear, while [8-3H]- Merck, Darmstadt) affixed with a paper wick and developed deoxyguanosine came from Amersham/Searle (Arlington overnight in methanol/water (1:1) (12). In representative ex- Heights, IL). All isotopes were tested for purity by thin-layer periments the nucleotides that remained at the origin were chromatography and appropriately diluted with unlabeled further fractionated into the mono-, di-, and triphosphates by nucleoside before use. EHNA was kindly provided by the a second development in sodium formate (pH 3.4) (13) or by Burroughs Wellcome Co. (Research Triangle Park, NC). All two-dimensional chromatography with a discontinuous buffer other reagents were of the highest grade obtainable from system (14). commercial sources. When tritiated isotopes were used, the nucleotide spots were cut out and extracted with 1 ml of 1 M TrisIHCl/0.7 M MgCl2 RESULTS at pH 7.4 before the addition of scintillation fluid (11). When Kinase Activities in Human Tissues. Table 1 shows the 14C isotopes were used, extraction of the product was unrtec- activities of adenosine kinase, deoxyadenosine kinase, deoxy- essary. inosine kinase, and deoxyguanosine kinase in newborn human Deaminase and phosphorylase activities were also deter- tissues as well as in adult human Jymphocytes and granulocytes. mined radiochemically, as previously described (8, 15). Guanosine and inosine kinase activities were undetectable (less Ion-Exchange Chromatography. Twenty milligrams of than 0.02 nmol/min per mg of protein) in any tissue, and are thymic cell extracts was dialyzed against 5 mM sodium phos- not shown. As can be seen, the ability to phosphorylate adeno- phate (pH 7.9) and applied to a 1-ml column of DE52-cellulose sine was widespread among human organs. On the contrary the (Whatman Ltd., Maidstone, Kent) equilibrated at 40 with the ability to phosphorylate deoxyadenosine and deoxyguanosine same buffer. After unbound material was washed with the was largely confined to the thymus and peripheral blood above buffer, the column was eluted with a linear gradient lymphocytes.
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