Genetic Dissection of Vasculitis, Myeloperoxidase-Specific Antineutrophil Cytoplasmic Autoantibody Production, and Related Traits in Spontaneous Crescentic Glomerulonephritis-Forming/Kinjoh Mice1
Genetic Dissection of Vasculitis, Myeloperoxidase-Specific Antineutrophil Cytoplasmic Autoantibody Production, and Related Traits in Spontaneous Crescentic Glomerulonephritis-Forming/Kinjoh Mice1
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DOI：
10.4049/jimmunol.176.6.3662
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发表时间：
2006-03
期刊：
影响因子：
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通讯作者：
Y. Hamano;K. Tsukamoto;M. Abe;G. Sun;Danqing Zhang;H. Fujii;S. Matsuoka;Masumi Tanaka;A. Ishida‐Okawara;H. Tachikawa;H. Nishimura;K. Tokunaka;S. Hirose;Kazuo Suzuki
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文献类型：
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作者：
Y. Hamano;K. Tsukamoto;M. Abe;G. Sun;Danqing Zhang;H. Fujii;S. Matsuoka;Masumi Tanaka;A. Ishida‐Okawara;H. Tachikawa;H. Nishimura;K. Tokunaka;S. Hirose;Kazuo Suzuki
自发性新月体肾炎/肾小球肾炎(SCG/Kj)小鼠是人类新月体肾炎和与髓过氧化酶(MPO)特异性抗中性粒细胞胞浆抗体(MPO-ANCA)产生相关的血管炎的模型。虽然疾病最初是由Fas基因突变(LPR)介导的，但SCG/KJ小鼠也存在非Fas易感遗传因素。为了确定这些因素，对雌性(B6×SCG/Kj)F2杂交小鼠进行了全基因组QTL定位。共检测到14个非Fas的QTL。肾小球肾炎QTL位于第1、10、13、16、17号染色体，血管炎位于第1、17号染色体，脾肿大位于第1号染色体，高丙球蛋白血症位于第1、2、4、6、7、11、13、17号染色体，抗核抗体位于第1、8、10、12号染色体，MPO-ANCA产生在第1、10号染色体。第1、2、7、13号染色体SCG/KJ的显著QTL分别命名为SCG-1~SCG-5，4、6、17、10号染色体的B6 QTL分别命名为Sxb-1~Sxb-4。第1和第10染色体上与MPO-ANCA产生连锁的两个基因座分别命名为Man-1和Man-2(针对MPO-ANCA)。虽然SCG-1和SCG-2都位于第一染色体上，并具有相同的功能，但有趣的是，MPO-ANCA的异常产生仅由SCG-2染色体片段的着丝粒半区Man-1控制。我们还检验了LPR突变和非Fas易感基因之间的上位性效应。QTL与前面描述的基因座有关，重点讨论它们的候选基因。
The spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mouse is a model of human crescentic glomerulonephritis and vasculitis associated with the production of the myeloperoxidase (MPO)-specific antineutrophil cytoplasmic autoantibody (MPO-ANCA). Although the disease is mediated initially by mutation of the Fas gene (lpr), SCG/Kj mice also have non-Fas predisposing genetic factors. To define these factors, genome-wide quantitative trait locus (QTL) mapping was performed on female (B6× SCG/Kj) F2 intercross mice. Fourteen non-Fas QTLs were identified. QTLs of glomerulonephritis were located on chromosomes 1, 10, 13, 16, and 17, vasculitis on chromosomes 1 and 17, splenomegaly on chromosome 1, hypergammaglobulinemia on chromosomes 1, 2, 4, 6, 7, 11, 13, and 17, antinuclear Ab on chromosomes 1, 8, 10, and 12, and MPO-ANCA production on chromosomes 1 and 10. Significant QTLs derived from SCG/Kj on chromosomes 1, 2, 7, and 13 were designated Scg-1 to Scg-5, respectively, and those derived from B6 on chromosomes 4, 6, 17, and 10 were designated Sxb-1 to Sxb-4, respectively. Two loci linked to MPO-ANCA production on chromosomes 1 and 10 were designated Man-1 and Man-2 (for MPO-ANCA), respectively. Although both Scg-1 and Scg-2 were on chromosome 1 and shared several functions, it was of interest that aberrant MPO-ANCA production was exclusively controlled by Man-1, the centromeric half region of the Scg-2 chromosomal segment. We also examined the epistatic effects between the lpr mutation and non-Fas susceptibility genes. QTLs are discussed in relation to previously described loci, with emphasis on their candidate genes.