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Genetic dissection of MPO-ANCA related systemic vasculitis-prone SCG/Kj mice.

MPO-ANCA 相关的系统性血管炎倾向 SCG/Kj 小鼠的基因解剖。

基本信息

批准号：
17591056
负责人：
HAMANO Yoshitomo
金额：
$ 2.24万
依托单位：
JUNTENDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591056/
关键词：
MPO-ANCA SCG Kj vasculitis glomerulonephritis crescent QTL

项目摘要

To define genetic factors for vasculitis, crescentic glomerulonephritis and MPOANCA production in the spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse, we performed genome-wide QTL mapping using female (B6×SCG/Kj) F_2 intercross mice. Fourteen non-Fas QTLs were identified: QTLs for glomerulonephritis were located on chromosomes 1, 10, 13, 16,and 17, those for vasculitis on chromosomes 1 and 17, and those for aberrant MPOANCA production on chromosomes 1 and 10. Statistically significant QTLs from SCG/Kj were designated Scg-1 to Scg-5 and those from B6 were designated Sxb-1 to Sxb-4. Two QTLs linked to aberrant MPO-ANCA were designated Man-1 and Man-2.We also investigated the immunopathological mechanism of spontaneous vasculitis, crescentic glomerulonephritis and abnormal MPOANCA production by flow cytometry. Correlation between values of leukocyte count including granulocytes, monocytes, T lymphocytes, B lymphocytes and dendritic cells (DCs) in peripheral blood and autoimmune phenotypes were statistically examined. As a result, increase of granulocytes, monocytes, CD4-CD8-double negative T cells and DCs were significantly associated with all of autoimmune phenotypes including MPO-ANCA and autoantibody levels, glomerulonephritis, vasculitis and splenomegaly. Subset study of dendritic cells revealed classical DCs, but not plasmacytoid DCs, were correlated with autoimmune phenotypes. Classical DCs were thus supposed to play some role in the disease pathogenesis. QTL analyses found out three to four significant loci for increase in cDCs and such loci were independent of previously known QTLs for autoimmunity in SCG/Kj. These facts suggested that QTLs for DCs acted as early susceptibility genes and caused initial activation of immune system in multistep pathogenesis of autoimmune diseases.

为了确定自发性月牙状肾小球肾炎/Kinjoh （SCG/Kj）小鼠血管炎、月牙状肾小球肾炎和MPOANCA产生的遗传因素，我们使用雌性（B6×SCG/Kj） F_2杂交小鼠进行了全基因组QTL定位。共鉴定出14个非fas qtl：肾小球肾炎qtl位于染色体1、10、13、16和17上，血管炎qtl位于染色体1和17上，畸变MPOANCA qtl位于染色体1和10上。来自SCG/Kj的qtl标记为SCG -1 ~ SCG -5，来自B6的qtl标记为Sxb-1 ~ Sxb-4。与异常MPO-ANCA相关的两个qtl被命名为Man-1和Man-2。通过流式细胞术研究自发性血管炎、新月形肾小球肾炎和异常MPOANCA产生的免疫病理机制。外周血白细胞计数（包括粒细胞、单核细胞、T淋巴细胞、B淋巴细胞和树突状细胞）与自身免疫表型的相关性进行统计学检验。因此，粒细胞、单核细胞、cd4 - cd8双阴性T细胞和dc的增加与所有自身免疫表型（包括MPO-ANCA和自身抗体水平）、肾小球肾炎、血管炎和脾肿大显著相关。树突状细胞的亚群研究显示，典型的树突状细胞与自身免疫表型相关，而浆细胞样树突状细胞与自身免疫表型无关。因此，经典dc被认为在疾病发病机制中起一定作用。QTL分析发现，在SCG/Kj中，有3 - 4个显著的cDCs增加位点，这些位点独立于先前已知的自身免疫QTL。这些事实表明，dc的qtl在自身免疫性疾病的多步骤发病过程中作为早期易感基因，引起免疫系统的初始激活。