Laboratory of Allergology & Pulmonary Diseases, Department of Pathology and Medical Biology, GRIAC Research Institute, University Medical Centre Groningen, University of Groningen, the Netherlands.
Am J Respir Cell Mol Biol. 2011 Aug;45(2):295-303. doi: 10.1165/rcmb.2009-0369OC. Epub 2010 Oct 22.
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.
小鼠变应性哮喘模型的特征是气道高反应性（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，我们旨在通过分析莱什曼原虫抗性（lmr）重组近交系（RC）品系的哮喘表型，在小鼠中鉴定新的哮喘易感基因。lmr RC 品系源自 C57BL/6 和 BALB/c 杂交，在两个背景下携带染色体 17（lmr1）和 9（lmr2）上的同源基因座。虽然染色体 9 上的 lmr2 基因座对抗 OVA IgE 和 AHR 有较小的背景特异性影响，但染色体 17 上的 lmr1 基因座介导了对 Th2 驱动的嗜酸性气道炎症的强烈影响，以及对抗 OVA IgE 和 AHR 的背景特异性影响。lmr1 基因座包含近 600 个多态性基因。为了缩小候选基因的数量，我们对 C.lmr1 RC 小鼠和 BALB/c 对照小鼠的肺组织进行了全基因组转录谱分析。我们鉴定了位于同源片段内的少数差异表达基因，包括 BALB/c 和 C57Bl/6 之间多态性的许多 MHC 基因。在携带 BALB/c 遗传背景下 C57Bl/6 单倍型的 C.B10-H2b RC 品系中分析哮喘表型，与 C.lmr1 相比，揭示了惊人相似的哮喘表型，表明位于 C.B10-H2b 同源片段内的差异表达基因是最有可能的候选基因，有助于减少与 lmr1 的 C57Bl/6 等位基因相关的哮喘表型。
