Croker B P, Gilkeson G, Morel L
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610-0275, USA.
Genes Immun. 2003 Dec;4(8):575-85. doi: 10.1038/sj.gene.6364028.
Interactions between Sle1 and other susceptibility loci were required for disease development in the NZM2410 model of lupus. Sle1 corresponds to at least three subloci, Sle1a, Sle1b, and Sle1c, each of which independently causes loss of tolerance to chromatin, but displays a distinctive immune profile. We have used congenic strains to analyze the interactions between the Sle1 subloci and other lupus susceptibility loci using Y autoimmunity accelerator (Yaa) and Faslpr as sensitizing mutations. Sle1 coexpressed with either one of these single susceptibility alleles resulted in a highly penetrant nephritis, splenomegaly, production of nephrophilic antibodies, and increased expression of B- and T-cell activation markers. Here, we show that only Sle1b interacted with Yaa to produce these phenotypes, suggesting that Sle1b and Yaa belong to the same functional pathway. Interactions between the three Sle1 loci and lpr resulted in lymphocyte activation and lupus nephritis, but a significant mortality was observed only for the Sle1a.lpr combination. This suggests a major role for the FAS pathway in keeping in check the loss of tolerance mediated by the Sle1 loci, especially for Sle1a. Our results illustrate the complexity of interactions between susceptibility loci in polygenic diseases such as lupus and may explain the clinical heterogeneity of the disease.
在新西兰黑鼠狼疮模型（NZM2410）中，疾病发展需要Sle1与其他易感基因座之间的相互作用。Sle1至少对应三个亚基因座，即Sle1a、Sle1b和Sle1c，每个亚基因座独立导致对染色质的耐受性丧失，但表现出独特的免疫特征。我们使用近交系通过Y染色体自身免疫加速因子（Yaa）和Faslpr作为致敏突变来分析Sle1亚基因座与其他狼疮易感基因座之间的相互作用。Sle1与这些单一易感等位基因中的任何一个共同表达都会导致高度显性的肾炎、脾肿大、嗜肾抗体的产生以及B细胞和T细胞活化标志物表达增加。在此，我们表明只有Sle1b与Yaa相互作用产生这些表型，这表明Sle1b和Yaa属于同一功能途径。三个Sle1基因座与lpr之间的相互作用导致淋巴细胞活化和狼疮性肾炎，但仅在Sle1a.lpr组合中观察到显著的死亡率。这表明FAS途径在控制由Sle1基因座介导的耐受性丧失中起主要作用，尤其是对于Sle1a。我们的结果说明了多基因疾病（如狼疮）中易感基因座之间相互作用的复杂性，并可能解释该疾病的临床异质性。
