Advertisement

Molecular Mechanism(s) of Deoxyribonucleoside Toxicity in T-Lymphoblasts

  • James M. Wilson
  • Beverly S. Mitchell
  • William N. Kelley
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 122B)

Abstract

The association of at least two inborn errors of purine metabolism with immunodeficiency diseases has made possible the investigation of these diseases at the molecular level. Adenosine deaminase (ADA) deficiency results in severe combined immunodeficiency disease with impairment of T- and B-lymphocyte function.1 Purine nucleoside Phosphorylase (PNP) deficiency has been associated with T-lymphocyte dysfunction in nine patients.2 The mechanism(s) whereby these enzyme deficiency states affect lymphocyte development and/or function has (have) not been fully elucidated. However, the recent findings of markedly elevated dATP levels in ADA-deficient erythrocytes3 and of dGTP levels in PNP-deficient erythrocytes4 provide support for the hypothesis that deoxyribonucleosides play an important role in the pathogenesis of the immune dysfunction in these two diseases and suggest that deoxyribonucleosides or their metabolites may be toxic to lymphoid cells.

Keywords

Adenosine Deaminase Ribonucleotide Reductase Severe Combine Immunodeficiency Purine Nucleoside Phosphorylase Severe Combine Immunodeficiency Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    E. R. Giblett, J. E. Anderson, F. Cohen, B. Pollar, and H. J. Meuwissen, Adenosine deaminase deficiency in two patients with severely impaired cellular immunity Lancet II:1067–1069 (1972).CrossRefGoogle Scholar
  2. 2.
    E. R. Giblett, A. J. Ammann, D. W. Wara, R. Sandman, and L. K. Diamond, Nucleoside Phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity Lancet I:1010–1013 (1975).CrossRefGoogle Scholar
  3. 3.
    M. S. Coleman, J. Donofrio, J. J. Hutton, L. Hahn, A. Daoud, B. Lampkin, and J. Dyminski, Identification and quantitation of adenine deoxynucleotides in erythrocytes of a patient with adenosine deaminase deficiency and severe combined immunodeficiency J. Biol. Chem. 253:1619–1626 (1978).PubMedGoogle Scholar
  4. 4.
    A. Cohen, L. J. Gudas, A. J. Ammann, G. E. J. Staal, and D. W. Martin, Jr., Deoxyguanosine triphosphate as a possible toxic metabolite in the immunodeficiency associated with purine nucleoside Phosphorylase deficiency J. Clin. Invest. 61:1405–1409 (1978).PubMedCrossRefGoogle Scholar
  5. 5.
    B. S. Mitchell, E. Mejias, P. E. Daddona, and W. N. Kelley, Purinogenic immunodeficiency diseases: selective toxicity of deoxyribonucleosides for T cells Proc. Natl. Acad. Sci. U.S.A. 75:5011–5014 (1978).PubMedCrossRefGoogle Scholar
  6. 6.
    B. Ullman, L. J. Gudas, A. Cohen, and D. W. Martin, Jr., Deoxyadenosine metabolism and cytoxicity in cultured mouse T lymphoma cells: a model for immunodeficiency disease Cell. 14:365–375 (1978).PubMedCrossRefGoogle Scholar
  7. 7.
    D. A. Carson, J. Kaye, and J. E. Seegmiller, Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside Phosphorylase deficiency: possible role of nucleoside kinase(s) Proc. Natl. Acad. Sci. U.S.A. 74:5677–5681 (1977).PubMedCrossRefGoogle Scholar
  8. 8.
    L. J. Gudas, B. Ullman, A. Cohen, and D. W. Martin, Jr., De-oxyguanosine toxicity in a mouse T lymphoma: relationship to purine nucleoside phosphorylase-associated immune dysfunction Cell. 14:531–538 (1978).PubMedCrossRefGoogle Scholar
  9. 9.
    J. F. Henderson and A. R. P. Paterson, “Nucleotide Metabolism: An Introduction,” Academic Press, New York (1973).Google Scholar
  10. 10.
    M. S. Hershfield, Apparent suicide inactivation of human lymphoblast S-adenosylhomocysteine hydrolase by 2’-deoxyadenosine and adenine arabinoside: a basis for direct toxic effects of analogs of adenosine J. Biol. Chem. 254:22–25 (1979).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1980

Authors and Affiliations

  • James M. Wilson
    • 1
  • Beverly S. Mitchell
    • 1
  • William N. Kelley
    • 1
  1. 1.Departments of Internal Medicine and Biological Chemistry, Human Purine Research CenterUniversity of Michigan Medical SchoolAnn ArborUSA

Personalised recommendations