Identification of the Mhc Region as an Asthma Susceptibility Locus in Recombinant Congenic Mice
Identification of the Mhc Region as an Asthma Susceptibility Locus in Recombinant Congenic Mice
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DOI：
10.1165/rcmb.2009-0369oc
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发表时间：
2011-08-01
影响因子：
6.4
通讯作者：
Van Oosterhout, Antoon J. M.
中科院分区：
文献类型：
--
作者：
Nawijn, Martijn C.;Piavaux, Benoit J. A.;Van Oosterhout, Antoon J. M.
过敏性哮喘小鼠模型的特点是气道高反应性(AHR)、Th2驱动的嗜酸性气道炎症、血清中高过敏原特异性IgE(抗OVA IgE)水平和气道重塑。由于哮喘易感性具有很强的遗传成分，我们的目的是通过分析利什曼原虫主要耐药(LMR)重组同源(RC)菌株的哮喘表型，在小鼠中发现新的哮喘易感基因。LMR RC株系来源于C57BL/6和BALB/c杂交，在17号染色体(1mr1)和9号染色体(Lmr2)上均有同源基因座。9号染色体上的lmr2基因座对抗OVA IgE和AHR的背景特异性效应较小，而17号染色体的lmr1基因座对Th2诱导的嗜酸性气道炎和抗OVA IgE和AHR的背景特异性效应起重要作用。Lmr1基因座包含近600个多态基因。为了缩小候选基因的数量，我们对C.lmr1 RC小鼠和BALB/c对照组小鼠的肺组织进行了全基因组转录图谱分析。我们发现了位于BALB/c和C57BL/6之间的少数差异表达基因，包括一些在BALB/c和C57BL/6之间多态的MHC基因。对携带BALB/c单倍型MHC基因的C.B10-H_2B RC株的哮喘表型分析显示，与C.lmr1相比，哮喘表型非常相似，表明位于C.B10-H_2B同源片段内的差异表达基因是与Lmr1的C57BL/6等位基因相关的哮喘表型减少的最有可能的候选基因。
Mouse models of allergic asthma are characterized by airway hyperreactivity (AHR), Th2-driven eosinophilic airway inflammation, high allergen-specific IgE (anti-OVA IgE) levels in serum, and airway remodeling. Because asthma susceptibility has a strong genetic component, we aimed to identify new asthma susceptibility genes in the mouse by analyzing the asthma phenotypes of the Leishmania major resistant (lmr) recombinant congenic (RC) strains. The lmr RC strains are derived from C57BL/6 and BALB/c intercrosses and carry congenic loci on chromosome 17 (lmr1) and 9 (lmr2) in both backgrounds. Whereas the lmr2 locus on chromosome 9 contributes to a small background-specific effect on anti-OVA IgE and AHR, the lmr1 locus on chromosome 17 mediates a strong effect on Th2-driven eosinophilic airway inflammation and background-specific effects on anti-OVA IgE and AHR. The lmr1 locus contains almost 600 polymorphic genes. To narrow down this number of candidate genes, we performed genome-wide transcriptional profiling on lung tissue from C. lmr1 RC mice and BALB/c control mice. We identified a small number of differentially expressed genes located within the congenic fragment, including a number of Mhc genes, polymorphic between BALB/c and C57Bl/6. The analysis of asthma phenotypes in the C.B10-H2b RC strain, carrying the C57Bl/6 haplotype of the Mhc locus in a BALB/c genetic background, reveals a strikingly similar asthma phenotype compared with C. lmr1, indicating that the differentially expressed genes located within the C.B10-H2b congenic fragment are the most likely candidate genes to contribute to the reduced asthma phenotypes associated with the C57Bl/6 allele of lmr1.