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 oft cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2197-2207 |
| Number of pages | 11 |
| Journal | Journal of Experimental Medicine |
| Volume | 191 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jun 19 2000 |
| Externally published | Yes |
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Keywords
- Apoptosis
- Immune deficiency
- Mitochondria
- Purine metabolism
- T lymphocyte
ASJC Scopus subject areas
- Immunology
Cite this
Mitochondrial basis for immune deficiency : Evidence from purine nucleoside phosphorylase-deficient mice. / Arpaia, Enrico; Benveniste, Patricia; Di Cristofano, Antonio; Gu, Yiping; Dalal, Ilan; Kelly, Susan; Hershfield, Michael; Pandolfi, Pier Paolo; Roifman, Chaim M.; Cohen, Amos.
In: Journal of Experimental Medicine, Vol. 191, No. 12, 19.06.2000, p. 2197-2207.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mitochondrial basis for immune deficiency
T2 - Evidence from purine nucleoside phosphorylase-deficient mice
AU - Arpaia, Enrico
AU - Benveniste, Patricia
AU - Di Cristofano, Antonio
AU - Gu, Yiping
AU - Dalal, Ilan
AU - Kelly, Susan
AU - Hershfield, Michael
AU - Pandolfi, Pier Paolo
AU - Roifman, Chaim M.
AU - Cohen, Amos
PY - 2000/6/19
Y1 - 2000/6/19
N2 - 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 oft cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.
AB - 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 oft cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.
KW - Apoptosis
KW - Immune deficiency
KW - Mitochondria
KW - Purine metabolism
KW - T lymphocyte
UR - http://www.scopus.com/inward/record.url?scp=0034686409&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034686409&partnerID=8YFLogxK
U2 - 10.1084/jem.191.12.2197
DO - 10.1084/jem.191.12.2197
M3 - Article
VL - 191
SP - 2197
EP - 2207
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 12
ER -