Testing the role of P2X7 receptors in the development of type 1 diabetes in nonobese diabetic mice.
Testing the role of P2X7 receptors in the development of type 1 diabetes in nonobese diabetic mice.
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DOI：
10.4049/jimmunol.1003733
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发表时间：
2011-04-01
期刊：
影响因子：
--
通讯作者：
Serreze DV
中科院分区：
文献类型：
--
作者：
Chen YG;Scheuplein F;Driver JP;Hewes AA;Reifsnyder PC;Leiter EH;Serreze DV
虽然P2rx7被认为是NOD小鼠的1型糖尿病（T1D）易感基因，但其潜在的致病作用尚未直接确定。为了测试这种可能性，我们产生了一个新的缺乏P2X7受体的NOD库存。P2X7消融未改变T1D的发展。先前的研究发现，CD38敲除（KO） NOD小鼠发生加速T1D的部分原因是CD4+不变NKT （iNKT）细胞和Foxp3+调节性t细胞（Tregs）的缺失。这些免疫调节性t细胞群对由adp -核糖基转移酶-2 （ART2）介导的P2X7受体adp -核糖基化激活的NAD诱导的细胞死亡（NICD）高度敏感。因此，我们想知道在双敲除（DKO） NOD缺乏P2X7和CD38的情况下，T1D加速是否会通过拯救NICD中的CD4+ inkt细胞和treg而被抑制。我们证明P2X7是由CD38缺乏引起的T1D加速所必需的。CD38 ko诱导的CD4+ inkt细胞和treg细胞的稳态缺陷通过P2X7的共消融得到纠正。cd38缺失NOD小鼠的T1D加速也需要ART2的表达。如果在CD38缺失的NOD小鼠中，P2X7的adp核糖基化增加是疾病加速的基础，那么CD38和ART2或CD38和P2X7共同消融应该会诱导类似的T1D发病率。然而，先前确定的CD38和ART2表达缺乏的NOD库存具有T1D抗性。目前的研究显示，在先前报道的缺乏ART2的NOD种群中，存在与消融的Cd38等位基因密切相关的T1D抗性基因，但在新产生的Cd38 /P2X7 DKO系中没有。
While P2rx7 has been proposed as a type 1 diabetes (T1D) susceptibility gene in NOD mice, its potential pathogenic role has not been directly determined. To test this possibility, we generated a new NOD stock deficient in P2X7 receptors. T1D development was not altered by P2X7 ablation. Previous studies found CD38 knockout (KO) NOD mice developed accelerated T1D partly due to a loss of CD4+ invariant NKT (iNKT) cells and Foxp3+ regulatory T-cells (Tregs). These immunoregulatory T-cell populations are highly sensitive to NAD induced cell death (NICD) activated by ADP-ribosyltransferase-2 (ART2)-mediated ADP-ribosylation of P2X7 receptors. Therefore, we asked if T1D acceleration was suppressed in a double knockout (DKO) NOD stock lacking both P2X7 and CD38 by rescuing CD4+ iNKT-cells and Tregs from NICD. We demonstrated P2X7 was required for T1D acceleration induced by CD38 deficiency. The CD38 KO-induced defects in homeostasis of CD4+ iNKT-cells and Tregs were corrected by co-ablation of P2X7. T1D acceleration in CD38-deficient NOD mice also requires ART2 expression. If increased ADP-ribosylation of P2X7 in CD38-deficient NOD mice underlies disease acceleration, then a comparable T1D incidence should be induced by co-ablation of both CD38 and ART2, or CD38 and P2X7. However, a previously established NOD stock deficient in both CD38 and ART2 expression is T1D resistant. The current study revealed the presence of a T1D resistance gene closely linked to the ablated Cd38 allele in the previously reported NOD stock also lacking ART2, but not in the newly generated CD38/P2X7 DKO line.
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影响因子：
7.3
作者：
Schenk, Ursula;Westendorf, Astrid M.;Grassi, Fabio
通讯作者：
Grassi, Fabio
影响因子：
12.8
作者：
Scheuplein, Felix;Rissiek, Bjoern;Serreze, David V.
通讯作者：
Serreze, David V.
影响因子：
5.3
作者：
Ohlrogge, W;Haag, F;Koch-Nolte, F
通讯作者：
Koch-Nolte, F
DOI：
10.1080/10446670310001593514
发表时间：
2002-12-01
期刊：
Developmental immunology
影响因子：
--
作者：
Haag, Friedrich;Freese, Dunja;Koch-Nolte, Friedrich
通讯作者：
Koch-Nolte, Friedrich
影响因子：
4.4
作者：
Scheuplein, Felix;Schwarz, Nicole;Koch-Nolte, Friedrich
通讯作者：
Koch-Nolte, Friedrich