Metabolic Causes of Immune Deficiency: Mechanisms and Treatment
In 1972, Dr Eloise R. Giblett, a haematologist, and her pediatrician colleagues described two unrelated children whose blood erythrocytes (and lymphocytes) lacked the purine enzyme adenosine deaminase (ADA)1. Both children suffered from a severe combined immune deficiency disease (SCID). At the same time a Danish group described two similar children with ADA deficiency associated with SCID2. It was suggested in these early reports that the defect in the immune system was caused by the enzyme deficiency. It was soon appreciated that the defect was inherited as an autosomal recessive, although it was some time before the enzyme deficiency could be mechanistically related to the immune deficiency. There was another major advance when Dr Giblett discovered another purine enzyme deficiency (purine nucleoside phosphorylase, PNP) in a patient with a selective cellular immune deficiency resembling the Nezelof syndrome3. The discovery of more PNP deficient patients showed that this was also an autosomal recessive disease4,5. Nowadays ADA and PNP deficiency are recognized as the primary cause of the associated immune deficiency.
KeywordsImmune Deficiency Adenosine Deaminase Ribonucleotide Reductase Purine Nucleoside Phosphorylase Deoxycytidine Kinase
Unable to display preview. Download preview PDF.
- 4.Stoop, J. W., Zegers, B. J. M., Hendrickx, G. F. M., Siegenbeek van Heukelom, L. H., Staal, G. E. J., de Bree, P. K., Wadman, S. K. and Ballieux, R. E. (1977). Purine nucleoside phosphorylase deficiency associated with selective cellular immunodeficiency. N. Engl. J. Med., 296, 651–5PubMedCrossRefGoogle Scholar
- 5.(1979). Enzyme Defects and Immune Dysfunction. Ciba Symp. 68, pp. 1–289. (Amsterdam, Oxford, New York: Excerpta Medica)Google Scholar
- 13.Rÿksen, G., Kuis, W., Wadman, S. K., Spaapen, L. J. M., Duran, M., Voorbrood, B. S., Staal, G. E. J., Stoop J. W. and Zegers, B. J. M. (1987). A new case of purine nucleoside phosphorylase deficiency: enzymologic, clinical and immunological characteristics. Pediatr. Res., 21, 137–41CrossRefGoogle Scholar
- 15.Borkowsky, W., Gershon, A. A., Shenkman, L. and Hirschhorn, R. (1988). Adenosine deaminase deficiency without immunodeficiency: clinical and metabolic studies. Pediatr. Res., 14, 885–9Google Scholar
- 16.(1985). Adenosine deaminase in disorders of purine metabolism and in immune deficiency. Ann. N. Y. Acad. Sci., 451, 1–342Google Scholar
- 20.Cohen, A., Gudas, L. J., Ammann, A. J., Staal, G. E. J. and Martin, D. W. Jr. (1978). Deoxyguanosine triphosphate as a possible toxic metabolite in the immunodeficiency associated with purine nucleoside phosphorylase deficiency. J. Clin. Invest., 61, 1404–9Google Scholar
- 29.Ullman, B., Gudas, L. J., Clift, S. M. and Martin, D. W. Jr. (1979). Isolation and characterization of purine nucleoside phosphorylase deficient T lymphoma cells and secondary mutants with altered ribonucleotide reductase: genetic model for immunodeficiency disease. Proc. Natl. Acad. Sci. USA, 76, 1074–8PubMedCrossRefGoogle Scholar
- 31.Scharenberg, J. G. M., Spaapen, L. J., Rijkers, G. T., Duran, M., Staal, G. E. J. and Zegers, B. J. M. (1986). Functional and mechanistic studies on the toxicity of deoxyguanosine for the in vitro proliferation and differentiation of human peripheral blood B lymphocytes. Eur. J. Immunol., 16, 381–7PubMedCrossRefGoogle Scholar
- 32.Hirschorn, R. (1980). Treatment of genetic diseases by allotransplantation. In Desnick, R. J. (ed.) Birth Defects. Original Article Series. Vol. 16, no. 1, pp. 429–44. March of DimesGoogle Scholar
- 35.Williams, D. A. and Orkin, S. H. (1985). Somatic gene therapy: current status and future prospects. J. Clin. Invest., 11, 1053–6Google Scholar