Belanger S, Tai L-H, Anderson S K, Makrigiannis A P
Institut de recherches cliniques de Montréal (IRCM), Laboratory of Molecular Immunology, Université de Montréal, Montréal, Quebec, Canada.
Genes Immun. 2008 Sep;9(6):509-21. doi: 10.1038/gene.2008.43. Epub 2008 Jun 5.
The mouse Ly49 and human killer cell immunoglobulin-like receptors (KIR) gene clusters encode activating and inhibitory class I MHC receptors on natural killer (NK) cells. A direct correlation between the presence of multiple activating KIR and various human autoimmune diseases including diabetes has been shown. Previous studies have implicated NK cell receptors in the development of diabetes in the non-obese diabetic (NOD) inbred mouse strain. To assess the contribution of Ly49 to NOD disease acceleration the Ly49 gene cluster of these mice was sequenced. Remarkably, the NOD Ly49 haplotype encodes the largest haplotype and the most functional activating Ly49 of any known mouse strain. These activating Ly49 include three Ly49p-related and two Ly49h-related genes. The NOD cluster contains large regions highly homologous to both C57BL/6 and 129 haplotypes, suggesting unequal crossing over as a mechanism of Ly49 haplotype evolution. Interestingly, the 129-like region has duplicated in the NOD genome. Thus, the NOD Ly49 cluster is a unique mix of elements seen in previously characterized Ly49 haplotypes resulting in a disproportionately large number of functional activating Ly49 genes. Finally, the functionality of activating Ly49 in NOD mice was confirmed in cytotoxicity assays.
小鼠Ly49和人类杀伤细胞免疫球蛋白样受体（KIR）基因簇在自然杀伤（NK）细胞上编码激活型和抑制型I类主要组织相容性复合体（MHC）受体。已证实，多种激活型KIR的存在与包括糖尿病在内的多种人类自身免疫性疾病之间存在直接关联。先前的研究表明，NK细胞受体在非肥胖糖尿病（NOD）近交小鼠品系的糖尿病发生过程中起作用。为了评估Ly49对NOD疾病加速的作用，对这些小鼠的Ly49基因簇进行了测序。值得注意的是，NOD Ly49单倍型编码已知任何小鼠品系中最大的单倍型和功能最强的激活型Ly49。这些激活型Ly49包括三个与Ly49p相关的基因和两个与Ly49h相关的基因。NOD基因簇包含与C57BL/6和129单倍型高度同源的大片段区域，提示不等交换是Ly49单倍型进化的一种机制。有趣的是，129样区域在NOD基因组中发生了复制。因此，NOD Ly49基因簇是先前已鉴定的Ly49单倍型中各种元件的独特组合，导致功能激活型Ly49基因数量过多。最后，通过细胞毒性试验证实了NOD小鼠中激活型Ly49的功能。
