Ge Yan, Brown Michael G, Wang Hongyang, Fu Shu Man
Department of Medicine and Center of Immunity, Inflammation and Regenerative Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
Methods Mol Biol. 2012;900:271-90. doi: 10.1007/978-1-60761-720-4_13.
Genetic and environmental factors contribute in the pathogenesis of systemic lupus erythematosus (SLE). Lupus nephritis, the most common and severe manifestation of SLE, involves inflammation in the kidney leading to loss of renal function. However, it is not clear what controls the progression of lupus nephritis; this is an important research question, considering its implications in clinical treatment of lupus nephritis. Finding genes that underlie the development and progression of lupus nephritis will shed light on this question. NZM2328 is a spontaneous mouse model for SLE. Most NZM2328 female mice develop autoantibodies (e.g., antinuclear antibody and anti-dsDNA antibody), glomerulonephritis (GN), and severe proteinuria between 5 and 12 months of age. In contrast, C57L/J mice fail to exhibit similar signs of autoimmune disease. We used classical genetics to map and identify SLE genes in offspring generated by backcrossing C57L/J to NZM2328. Quantitative trait loci (QTL) controlling acute (Agnz1 and Agnz2) and chronic (Cgnz1) GN features were uncovered by the analysis. To verify the Cgnz1 and Agnz1 on distal mouse chromosome 1, we produced the NZM23238.C57Lc1 (Lc1) congenic strain, which replaced NZM2328 Cgnz1 and Agnz1 alleles with those derived from C57L/J. The development of acute GN and chronic GN was markedly reduced in Lc1 mice, confirming the linkage findings. Further mapping by the generation of intrachromosomal recombinants of NZM2328.Lc1 support the thesis that acute GN and chronic GN are under separate genetic control.
遗传和环境因素在系统性红斑狼疮（SLE）的发病机制中起作用。狼疮性肾炎是SLE最常见和最严重的表现形式，涉及肾脏炎症，导致肾功能丧失。然而，目前尚不清楚是什么控制着狼疮性肾炎的进展；考虑到其对狼疮性肾炎临床治疗的影响，这是一个重要的研究问题。找到狼疮性肾炎发生和发展的潜在基因将有助于阐明这个问题。NZM2328是一种SLE的自发小鼠模型。大多数NZM2328雌性小鼠在5至12月龄时会产生自身抗体（如抗核抗体和抗双链DNA抗体）、肾小球肾炎（GN）和严重蛋白尿。相比之下，C57L/J小鼠未表现出类似的自身免疫性疾病迹象。我们利用经典遗传学方法对C57L/J与NZM2328回交产生的后代中的SLE基因进行定位和鉴定。通过分析发现了控制急性（Agnz1和Agnz2）和慢性（Cgnz1）GN特征的数量性状位点（QTL）。为了验证小鼠1号远端染色体上的Cgnz1和Agnz1，我们培育了NZM23238.C57Lc1（Lc1）近交系，该品系用来自C57L/J的等位基因取代了NZM2328的Cgnz1和Agnz1等位基因。Lc1小鼠急性GN和慢性GN的发生率明显降低，证实了连锁研究结果。通过生成NZM2328.Lc1的染色体内重组体进行进一步定位，支持急性GN和慢性GN受独立遗传控制的论点。
