title: Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice.
abstract: 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.
authors.affiliation: Division of Immunology/Allergy, Department of Paediatrics, Hospital for Sick Children, The University of Toronto, Ontario, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Arpaia
authors.forename: P
authors.initials: P
authors.lastname: Benveniste
authors.forename: A
authors.initials: A
authors.lastname: Di Cristofano
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.forename: I
authors.initials: I
authors.lastname: Dalal
authors.forename: S
authors.initials: S
authors.lastname: Kelly
authors.forename: M
authors.initials: M
authors.lastname: Hershfield
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: C M
authors.initials: CM
authors.lastname: Roifman
authors.forename: A
authors.initials: A
authors.lastname: Cohen
mesh_terms: D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D003602:Cytotoxicity, Immunologic; D003848:Deoxyguanine Nucleotides / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency* / Q000235:genetics*; D016511:Severe Combined Immunodeficiency / Q000209:etiology*; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology
chemical_list: D003848:Deoxyguanine Nucleotides; C029603:deoxyguanosine triphosphate; D011683:Purine-Nucleoside Phosphorylase