We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in humans. Similar to the human disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased numbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.
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19 June 2000
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June 19 2000
Mitochondrial Basis for Immune Deficiency: Evidence from Purine Nucleoside Phosphorylase–Deficient Mice
Enrico Arpaia,
Enrico Arpaia
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
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Patricia Benveniste,
Patricia Benveniste
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
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Antonio Di Cristofano,
Antonio Di Cristofano
cDepartment of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, and the Graduate School of Medical Sciences, Cornell University, New York, New York 10021
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Yiping Gu,
Yiping Gu
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
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Ilan Dalal,
Ilan Dalal
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
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Susan Kelly,
Susan Kelly
dDepartment of Medicine, Duke University Medical Center, Chapel Hill, North Carolina 27710
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Michael Hershfield,
Michael Hershfield
dDepartment of Medicine, Duke University Medical Center, Chapel Hill, North Carolina 27710
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Pier Paolo Pandolfi,
Pier Paolo Pandolfi
cDepartment of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, and the Graduate School of Medical Sciences, Cornell University, New York, New York 10021
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Chaim M. Roifman,
Chaim M. Roifman
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
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Amos Cohen
Amos Cohen
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
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Enrico Arpaia
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
Patricia Benveniste
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
Antonio Di Cristofano
cDepartment of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, and the Graduate School of Medical Sciences, Cornell University, New York, New York 10021
Yiping Gu
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
Ilan Dalal
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
Susan Kelly
dDepartment of Medicine, Duke University Medical Center, Chapel Hill, North Carolina 27710
Michael Hershfield
dDepartment of Medicine, Duke University Medical Center, Chapel Hill, North Carolina 27710
Pier Paolo Pandolfi
cDepartment of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, and the Graduate School of Medical Sciences, Cornell University, New York, New York 10021
Chaim M. Roifman
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
Amos Cohen
aDivision of Immunology/Allergy, Department of Paediatrics and the Department of Immunology,
bInfection, Immunity, Injury and Repair Program, Research Institute, The Hospital for Sick Children, The University of Toronto, Toronto, Ontario MSG 1X8, Canada
eDepartment of Immunology, University of Toronto, Toronto, Ontario MSG 1X8, Canada
P. Benveniste and E. Arpaia contributed equally to this work.
Abbreviations used in this paper: ADA, adenosine deaminase; Δψm, mitochondrial membrane potential; DN, double negative; DP, double positive; MNGIE, neurogastrointestinal encephalomyopathy; PNP, purine nucleoside phosphorylase; SP, single positive; TP, thymidine phosphorylase.
Received:
January 24 2000
Revision Requested:
March 20 2000
Accepted:
April 03 2000
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 2000 The Rockefeller University Press
2000
The Rockefeller University Press
J Exp Med (2000) 191 (12): 2197–2208.
Article history
Received:
January 24 2000
Revision Requested:
March 20 2000
Accepted:
April 03 2000
Citation
Enrico Arpaia, Patricia Benveniste, Antonio Di Cristofano, Yiping Gu, Ilan Dalal, Susan Kelly, Michael Hershfield, Pier Paolo Pandolfi, Chaim M. Roifman, Amos Cohen; Mitochondrial Basis for Immune Deficiency: Evidence from Purine Nucleoside Phosphorylase–Deficient Mice. J Exp Med 19 June 2000; 191 (12): 2197–2208. doi: https://doi.org/10.1084/jem.191.12.2197
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