Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase
Bb2Bb3 regulation of murine Lyme arthritis is distinct from Ncf1 and independent of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase
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DOI：
10.1016/s0002-9440(10)62050-0
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发表时间：
2005-09-01
影响因子：
6
通讯作者：
Weis, JJ
中科院分区：
文献类型：
--
作者：
Crandall, H;Ma, Y;Weis, JJ
几个数量性状基因座调节小鼠莱姆病关节炎的严重程度已被映射，包括一个高度显着的连锁发现5号染色体上，称为Bb 2Bb 3。在该区域内，吞噬细胞烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶的Ncf 1基因最近被确定为类风湿性关节炎啮齿动物模型中关节炎严重程度的主要调节因子，该作用归因于活性氧的保护特性。为了评估Ncf 1在莱姆关节炎中的作用，我们将来自严重关节炎C3 H/He小鼠的Bb 2 Bb 3基因渗入到轻度关节炎C57 BL/6小鼠中。这增加了莱姆病关节炎的严重程度，而相互转移则保护了疾病。在Ncf 1基因中发现了一个单核苷酸多态性，该多态性不影响Ncf 1的蛋白质序列或表达。虽然来自C57 BL/6小鼠的多形核白细胞比来自C3 H/He小鼠的多形核白细胞产生更大的氧化爆发，但对Bb 2 Bb 3同源小鼠的研究表明，这种差异与Ncf 1等位基因无关。此外，莱姆病关节炎的严重程度没有改变小鼠缺乏Ncf 1或Gp 91 phox亚基的NADPH氧化酶复合物。总之，这些结果表明Ncf 1不是调节莱姆关节炎的候选基因，并揭示莱姆关节炎独立于NADPH氧化酶活性，将其与其他类风湿性关节炎模型区分开来。
Several quantitative trait loci regulating murine Lyme arthritis severity have been mapped, including a highly significant linkage found on chromosome 5, termed Bb2Bb3. Within this region, the Ncf1 gene of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase has recently been identified as a major regulator of arthritis severity in rodent models of rheumatoid arthritis, an effect attributed to protective properties of reactive oxygen species. To assess the role of Ncf1 in Lyme arthritis, we introgressed Bb2Bb3 from severely arthritic C3H/He mice onto mildly arthritic C57BL/6 mice. This increased Lyme arthritis severity, whereas the reciprocal transfer conferred protection from disease. A single nucleotide polymorphism was identified in the Ncf1 gene that did not influence the protein sequence or expression of Ncf1. Although polymorphonuclear leukocytes from C57BL/6 mice generated a greater oxidative burst than polymorphonuclear leukocytes from C3H/He mice, studies with the Bb2Bb3 congenic mice demonstrated this difference was not linked to Ncf1 alleles. Furthermore, Lyme arthritis severity was not altered in mice lacking either the Ncf1 or Gp91phox subunits of the NADPH oxidase complex. Together, these results argue that Ncf1 is not a candidate gene for regulation of Lyme arthritis and reveal Lyme arthritis to be independent of NADPH oxidase activity, distinguishing it from other models of rheumatoid arthritis.