Role of Purines in Lymphocyte Function *

Role of Purines in Lymphocyte Function * H. Kyle Webster, Ph.D. A II cells require a balanced supply disease (SCID) whose RBC and neous hypersensitivity and reduced of purines for growth, proliferation other tissues lacked the enzyme responsiveness of lymphocytes to and sllrvival. The major roles of adenosine deaminase (ADA). The mitogens, allogeneic cells, and other purines in cellular metabolism and nex t year ten more cases of SCID antigens. 1 There is severe h ypo function are given in Table I. In associated ADA deficiency were re gammagloblulinaemia 0 r agamma Figure I, a simplified outline is ported. The parents of affected globulinaemia with no evidence of shown of the basic pathways by children were found to have re specific antibody synthesis. Such which purines are metabolised. The duced RBC ADA activity indicating individuals are prone to increasingly purpose of this article is to review an autosomal recessive form of the severe infections with eventual fatal those aspects of purines that appear disease. Thus it appeared that at outcome in the absence of success unique to lymphocytes and thus least some forms of immunodefi ful therapy. Successful immuno their functions in immune pro ciency disease were "inborn errors logical reconstitution has been cesses. Basically, the rationale for of metabolism." achieved in ADA deficient SCID this focus comes from the involve Adenosine deaminase (adenine patients with histocompatible bone ment of purines in immunodefi aminohydrolase) (E.C. 3.5.4.4) marrow transplantation.6 Another ciency diseases a nd the use 0 f catalyses the irreversible deamina therapy effective in some indivi- purine analogues as immunosup tion of adenosine to inosine or de pressive agents. oxyadenosine to deoxyinosine. ADA has a monomeric structure Table 1 Purine functions. Purine catabolism and immuno and a molecular weight of 38,000 deficiency diseases daltons when extracted from RBC. 1. Energy metabolism (A TP) The discovery t hat hereditary RBC ADA is the smallest and sim 2. Monomeric precursors of DNA and disturbances in purine metabolism plest form of the enzyme. Several and RNA interfere with lymphocyte function different tissue-specific isozymes has produced a n intense interest exist consisting of two catalytically 3. Structural components , a) Coenzymes (FAD, NAD, NADP) ' .' over the past 10 years in the bio active subunits identical to RBC chemistry of the lymphoid immune ADA - combined with a dimeric b) Methyl donor (SAM) system. 1-3 Three lymphocyte conversion factor or binding pro 4. Regulatory roles enzymes have been associated with tein of 190,000 daltons. The pro a) Metabolic signals (cAMP/cGMP) immunodeficiency diseases: adeno perties of the human red cell ADA b) Allosteric effects sine deaminase, purine nucleoside enzyme h ave been described in 5. Physiological roles phosphorylase and 5'-nucleotidase. detail by Daddona and Kelley. 5 a) Smooth muscle Adenosine deaminase defiCiency ADA occurs in most body tissues. b) Platelets The first case of immunodefi Especially high levels of ADA en c) Neurotransmission ciency disease associated with an in zyme activity are found in thymus, herited purinogenic defect in lym spleen and other lymphoid tissues. phocytes was reported by Eloise ADA deficiency is characterised *From the Department of Immunology and 4 by both T and B lymphocyte de Giblett and colleagues in 1972. Biochemistry. Anned Forces Research Institute They described two children wi th fects. There is a profound lympho of Medical Sciences (AFRIMS). Bangkok. Thai severe combined immunodeficiency penia, absence of delayed cuta land :~ 311 312 WEBSTER cytes;1O and, 4) decreased S-adeno R-5-P+ATP I "'PHOSPHORIBOSYLPYROPHOSPHATE sylhomocyt-eine hydrolase activity resulting in accumulation 0 f S 'rGLUTAMINE adenosylhomocyteine which can in PHOSPHORIBOSYLAMINE I hibit S-adenosylmethionine mediat cAMP ~GLYCINE cGMP ed me thylation reactions. ll This FORMATE GTP).' latter effect may be due to the high 2~ATP (N A) UI rGLUTAMINE~ (N A) " ~C~ , , level of deoxyadenosine which acts ADP ~ dADP rASPARt:ATE dGDP ~ GDP as a "suicide" inhibitor of S-adeno sylhomocyteine hydrolase. '2 A .!P~ ,Jp~GLp combination of these biochemical changes may p r.ovide a plausible basis for the lymphocyte dysfunc " ·'''1::')'' ''''"f'''' '""f:"''\'' tion in ADA deficiency. The "r.:+"~,,,~DENINE HYPOXANTHINE ~XANTHINE ~ GUANINE·) 20 ~' sequence of toxic events may be as HOMOCYSTEINE URIC ACID follows. The absence of ADA acti S-ADENOSYLHOhlOCYSTEINE vity leads to accumulation of adenosine (AR) and deoxyadeno t" S-ADENOSYLMETHIONINE sine. Deoxyadenosine (dAR) is acted on by nucleoside kinase (dAR Fig. 1 Purine pathway enzymes kinase occurs specifically in lymp I) Phosphoribosyl pyrophosphate synthetase (EC 2.7-6. 1), hoid tissues) producing increased 2) Amidophosphoribosyl transferase (EC 2.4.2 .14), ("trapped") dATP. The accumulat 3) (De Novo pathway enzymes), ed dATP acts to allosterically in 4) IMP dehydrogenase (EC 1.2.1.14), h ibit ribonucleotide reductase 5) GMPsynthetase (EC 6.3.5 .2), which leads to disruption of DNA 6) Adenylosuccinate (AMPS) synthetase (EC 6.3.4.4), synthesis and thus lymphocyte 7) Adenylosuccinate lyase (EC 4.3.2.2), killing. An interesting alternative 8) GMP reductase (EC 1.6.6.8), hypothesis has been recently 9) AMP deaminase (EC 3 .5.4.6), advanced by Carson and collea 10) 5' -nucleotidase (EC 3.1.3 .5), gues l3 who proposed that the II) Adenosine kinase (EC 2.7.1.20), elevated dATP levels kill rna ture re 12) Hypoxanthine - Guanine phospho ribosyl transferase (EC 2.4.2.8), sting T lymphocytes by depleting 13) Adenine phosphoribosyl transferase (EC 2.4.2 .7 ), ATP levels. This could well be a 14) Adenosine deaminase (EC 3.5.4.4), contributing biochemical factor 15) Purine nucleoside phosphorylase (EC 2.4.2.1), that in combination with dATP 16) Guanine deaminase (EC 3.5.4.3), mediated ribonucleotide reductase 17) Xanthine oxidase (EC 1.2.3.2), inhibition produces an overwhelm 18) Ribonucleotide reductase, ing metabolic disruption in ADA 19) Protein carboxymethylase (EC 2.1.1.24), deficient lymphocytes. 20) S-adenosylhomocysteine hydrolase (EC 3.3.1.1), 21) Adenylate cyclase (EC 4.6.1.1), Purine nucleoside phosphorylase 22) Guanylate cyclase (EC 4.6 .1.2) deficiency Following the discovery of the duals involves infusion of nonnal A number of biochemical mecha association of ADA deficiency with irradiated RBC as a source of nisms have been proposed to ex SCID, a second purine defect was encapsulated ADA which can result plain how ADA deficiency affects discovered during active screening in restoration of immune re the function of lymphocytes. No of patients for ADA deficiency. sponses. 7 This fonn of enzyme re single proposal has as yet been to Again in 1975, Eloise Giblett and placement therapy is particularly in tally accepted. There are four basic colleagues described an association teresting in that the RBC enzyme biochemical changes observed in of purine nucleoside phosphorylase acts to correct the biochemical ADA-SCm patients. I) elevated (PNP) deficiency with a selective problem in ADA defective lympho plasma adenosine and deoxyadeno T-Iymphocyte dysfunction. 14 Like cytes. This observation suggests sine;8 2) accumulation of adenosine ADA deficiency PNP deficiency is---a an important relationship between deoxynucleotides, especially dATP, autosomal recessive disease. RBC and lymphocytes in tenns of in lymphocytes and RBC;9 3) in Purine nucleoside phosphorlyase systemic purine homeostasis. creased cAMP levels ~j"1 lympho- (purine riboside - orthophosphate PURINES IN LYMPHOCYTE FUNCTION 313 ribosyl transferase) (EC 2.4.2.1) hibit ribonucleotide reductase cells could explain in part the dif catalyses the reversible coversion of which leads to disruption of DNA ferential behavior of these cells in guanosine and deoxyguanosine to synthesis. dGR and dGTP appear PNP-deficiency disease. guanine and of inosine and deoxy to be extremely toxic to T-suppres Another interesting observation inosine to hypoxanthine. The en sor lymphocytes but less so to T has been the demonstration of a zyme occurs in most tissues with helper lymphocytes. 17 This d if lymphocyte ecto-ADPase.23 During particularly high Ievels in RBC. ferential toxicity may explain the platelet aggregation ADP is released Red cell PNP is a trimer composed sparing of antibody mediated im into the extracellular space. Given of identical 28,000 dalton subunits mune function in PNP deficiency. ADP as a physiological sub with each subunit having one sub A basically unaddressed but strate, lymphocytes thus have strate-binding site. ls The RBC fundamental concern in trying to an ectoenzyme system for loca isozyme shows a seven-banded mechanistically explain the immune lised production of adenosine (viz: pattern on starch gel electrophore defect in both PNP and ADA de ADP ADP-ase. AMP 5'-NTD-ase AR). sis with the slowest moving band ficiency is how the observed bio Adenosine: role in normal lym representing the primary gene pro chemical changes relate to the onto phocvte function. duct; other bands represent postge geny of T and B lymphocytes in The biochemical consequences nic modifications. 16 these disease s ta tes. Research is of ADA and PNP immunodefici Clinically, PNP deficient indivi currently underway on this issue ency diseases suggest that pathways duals have a severe lymphopenia and results from these studies may of purine nucleoside catabolism are with marked loss of T-Iymphocyte improve our understanding of the essential to norma I Iymphocy te function. There appears to be a fundamental role of purines in im function . Perhaps more important total loss of T suppressor lympho mune cell function. ly they suggest that the nucleosides, cytes. 17 B-Iymphocyte functions adenosine a nd guanosine, whose are intact with no impairment of 5'Nucleotidase deficiency turnover is regulated by these cata specific antibody synthesis to im Deficiency of lymphocyte ecto bolic pathways have critical roles in munising antigens. Most children 5' nucleotidase has been reported in cellular function.

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