IMMUNODEFICIENCY CAUSED BY PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY - 04/09/11

Doi : 10.1016/S0889-8561(05)70139-9

Amos Cohen, PhD ^{^{*
Division of Immunology and Allergy, Department of Paediatrics, Infection, Immunity, Injury, and Repair Program, Research Institute, The University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada}}, Eyal Grunebaum, MD ^{^{*
Division of Immunology and Allergy, Department of Paediatrics, Infection, Immunity, Injury, and Repair Program, Research Institute, The University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada}}, Enrico Arpaia, PhD ^{^{*
Division of Immunology and Allergy, Department of Paediatrics, Infection, Immunity, Injury, and Repair Program, Research Institute, The University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada}}, Chaim M. Roifman, MD, FRCPC, FCACB ^{^{*
Division of Immunology and Allergy, Department of Paediatrics, Infection, Immunity, Injury, and Repair Program, Research Institute, The University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada}}

Résumé

Purine nucleoside phosphorylase (PNP) is a key enzyme in the purine salvage pathway with adenosine deaminase (ADA). Inherited deficiency of either one of two purine salvage enzymes results in severe combined immunodeficiency (SCID) in humans.^{32 Giblett E.R., Ammann A.J., Wara D.W. , et al. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity Lancet 1975 ; 1 : 1010 [cross-ref]

Cliquez ici pour aller à la section Références, 33 Giblett E.R., Anderson J.E., Cohen F. , et al. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity Lancet 1972 ; 2 : 1067 [cross-ref]

Cliquez ici pour aller à la section Références, 50 Markert M.L. Purine nucleoside phosphorylase deficiency Immunodefic Rev 1991 ; 3 : 45

Cliquez ici pour aller à la section Références}

One of the striking features of ADA and PNP deficiencies is the selective effect on the immune system, although the activities of these enzymes are missing in every cell in the body.^{50 Markert M.L. Purine nucleoside phosphorylase deficiency Immunodefic Rev 1991 ; 3 : 45

Cliquez ici pour aller à la section Références} The biochemical mechanism(s) explaining the pathology of PNP deficiency attempts to address the specificity of this disease toward the immune system.^{50 Markert M.L. Purine nucleoside phosphorylase deficiency Immunodefic Rev 1991 ; 3 : 45

Cliquez ici pour aller à la section Références, 68 Resta R., Thompson L.F. SCID: The role of adenosine deaminase deficiency Immunol Today 1997 ; 18 : 371

Cliquez ici pour aller à la section Références}

Enzyme deficiencies can cause deleterious phenotypes as a result of lack of product of the enzymatic reaction or as a consequence of the cytotoxicity of the accumulating substrates. The lack of products in PNP deficiency is unlikely to contribute to the immune deficiency because deficiency of the next enzyme in the purine salvage pathway hypoxanthine-guanine phosphoribosyl transferase (HGPRT) causes Lesch-Nyhan syndrome with normal immune function.^{62 Page T., Bakay B., Nissinen E. , et al. Hypoxanthine-guanine phosphoribosyltransferase variants: Correlation of clinical phenotype with enzyme activity J Inher Metab Dis 1981 ; 4 : 203

Cliquez ici pour aller à la section Références} Of the four purine nucleoside substrates of the PNP reaction, inosine, deoxyinosine, guanosine, and deoxyguanosine, only deoxyguanosine has an alternative metabolic fate (i.e., phosphorylation by deoxyguanosine kinase) (Figure 1).^{28 Eriksson S., Arner E., Spasokoukotskaja T. , et al. Properties and levels of deoxynucleoside kinases in normal and tumor cells: Implications for chemotherapy Adv Enzyme Regul 1994 ; 34 : 13

Cliquez ici pour aller à la section Références, 90 Wang L., Hellman U., Eriksson S. Cloning and expression of human mitochondrial deoxyguanosine kinase cDNA FEBS Lett 1996 ; 390 : 39

Cliquez ici pour aller à la section Références} Deoxyguanosine is the only logical candidate to mediate the lymphoid abnormalities observed in PNP deficiency. The challenge remains to explain the metabolic, biochemical, and cellular mechanisms that lead to the unique lymphoid specificity of PNP deficiency despite its ubiquitous expression.

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Plan

PURINE NUCLEOSIDE METABOLIC PATHWAYS: THE ROLE OF PURINE NUCLEOSIDE PHOSPHORYLASE

METABOLIC CONSEQUENCES OF PURINE NUCLEOSIDE PHOSPHORYLASE DEFICIENCY

MODELS FOR PNP DEFICIENCY

Cell Cultures

Animal Models

IMMUNE DEFICIENCY DISEASES WITH ABNORMALITIES IN RIBONUCLEOTIDE REDUCTASE ACTIVITY AND DNA REPAIR

Thymidine Phosphorylase Deficiency

Adenosine Deaminase Deficiency

Ataxia-Telangiectasia Gene Product

Human Purine Nucleoside Phosphorylase Deficiency

Genetic and Metabolic Features of PNP Deficiency

Effect of Purine Nucleoside Phosphorylase Deficiency on the Immune System

Treatment and Prognosis

Address reprint requests to Chaim M. Roifman, MD, FRCPC, FCACB, Division of Immunology and Allergy, Department of Paediatrics, Infection, Immunity, Injury, and Repair Program, Research Institute, The University of Toronto and, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8 Canada, e-mail: [email protected]