Identification of QTLs that modify peripheral neuropathy in NOD.H2b-Pdcd1-/- mice
Identification of QTLs that modify peripheral neuropathy in NOD.H2b-Pdcd1-/- mice
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DOI：
10.1093/intimm/dxp020
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发表时间：
2009-05-01
影响因子：
4.4
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Jiang, Fang;Yoshida, Taku;Okazaki, Taku
非肥胖糖尿病（NOD）小鼠品系易于发展各种自身免疫综合征，包括I型糖尿病（T1 DM）、涎腺炎、甲状腺炎和胰腺炎。虽然T1 DM的遗传基础已被广泛分析，但改变其他自身免疫表型的遗传因素在很大程度上是未知的。我们最近报道了具有抗致糖尿病MHC单倍型（H-2（B））和程序性细胞死亡1（PD-1）缺陷（NOD. H2（B）-Pdcd 1（-/-）小鼠）的NOD小鼠免受T1 DM的影响，但发展各种组织特异性自身免疫性疾病，包括由于自身免疫性神经炎、涎腺炎和胃炎引起的周围神经病变。在本研究中，我们产生[（C57 BL/6 x NOD.H2（B））（F1）3 NOD-H2（B）]（BC 1）-Pdcd 1（-/-）小鼠以筛选修饰T1 DM以外的自身免疫表型的非MHC数量性状位点（QTL）。我们确定了7个QTL的周围神经病变和神经炎，1个QTL的胰岛炎，4个QTL的胃炎，2个QTL的涎腺炎和7个QTL的血管炎的整个基因组，并指定为Annp位点的自身免疫由于非MHC基因的多态性NOD小鼠和PD-1缺乏症。Annp 1、5、6和7与报道的T1 DM基因座（分别为Idd 3、9、15和2）重叠，表明这些基因座不仅修饰T1 DM，还修饰其他自身免疫表型。在14个Annp位点中，NOD等位基因在9个位点上起促进作用，在其余位点上起保护作用。Annp基因座中有一半与单一表型相关，而其他7个基因座与两种以上表型相关。这些结果表明，NOD遗传背景中含有多种QTL，这些QTL通过器官特异性或器官非特异性方式修饰自身免疫表型。
The non-obese diabetic ( NOD) mouse strain is prone to developing various autoimmune syndromes including type I diabetes mellitus (T1DM), sialadenitis, thyroiditis and pancreatitis. Although the genetic basis of T1DM has been extensively analyzed, genetic factors that modify the other autoimmune phenotypes are largely unknown. We have recently reported that NOD mice with anti-diabetogenic MHC haplotype (H-2(b)) and programmed cell death 1 (PD-1) deficiency (NOD.H2(b)-Pdcd1(-/-) mice) are protected from T1DM but develop various tissue-specific autoimmune diseases including peripheral neuropathy due to autoimmune neuritis, sialadenitis and gastritis. In the present study, we generated [(C57BL/6 x NOD.H2(b))(F1) 3 NOD-H2(b)] (BC1)-Pdcd1(-/-) mice to screen non-MHC quantitative trait loci (QTLs) that modify autoimmune phenotypes other than T1DM. We identified seven QTLs for peripheral neuropathy and neuritis, one QTL for insulitis, four QTLs for gastritis, two QTLs for sialadenitis and seven QTLs for vasculitis throughout the genome and designated them as Annp loci for autoimmunity due to polymorphisms of non-MHC genes in NOD mice and PD-1 deficiency. Annp1, 5, 6 and 7 overlapped with reported loci for T1DM (Idd3, 9, 15 and 2, respectively), suggesting that these loci modify not only T1DM but also other autoimmune phenotypes. NOD allele was promotive at 9 of 14 Annp loci, while NOD allele was protective at the other loci. Half of Annp loci associated with a single phenotype, while the other seven loci associated with more than two phenotypes. These results indicate that NOD genetic background harbors various QTLs that modify autoimmune phenotypes either by organ-specific or by organ-non-specific manner.