Role of the allelic polymorphism of osteopontin gene on the pathogenesis and development of autoimmune glomerulonephritis

MRL/Mp·lpr/lpr（MRL/lpr）的老鼠（MRL/lpr）的缺陷是一个众所周知的自动免疫疾病模型，包括狼疮肾病，而C3 H/HeJ-lpr/lpr（C3 H/lpr）老鼠则不开发这种疾病。我们对Glomerulonepritis的发展进行了全基因组筛查，定义为病理学清单，使用179个MRL/lpr ×（MRL/lpr × C3 H/lpr）F1背部交叉小鼠和266个（MRL/lpa × C3 H/lpr）F2交叉小鼠，使用526个F2交叉小鼠对染色体5进行精确映射。作为一个结果，Glomerulonepritis的最重要链接被映射到D5 Mit 115在染色体5的位置上的相同别名的骨斑蛋白（OPN）基因，指示MRL等位基因的主导模式的可持续继承。为了澄清MRL和C3 H菌株在Glomerulonepritis的发展机制之间的功能差异，我们已经对从两种菌株中产生的多态OPN菌株的功能分析进行了分析，在无细胞系统中协同准备，使用短期的共同培养系统与MRL或C3 H菌株的分蓝细菌。MRL-OPN induced higher mRNA expression and production of IgG3 as well as cytokines including TNF-\and IL-1\than C3H-OPN. These findings suggest that an allelic polymorphism of OPN may play a critical role for the development of glomerulonephritis in MRL/lpr mice。

An MRL/Mp・lpr/lpr strain of mice(MRL/lpr)with deficit in Fas is a well-known model of autoimmune diseases including lupus nephritis, while C3H/HeJ-lpr/lpr(C3H/lpr)mice do not develop the diseases. We performed genome wide screening of susceptibility loci to the development of glomerulonephritis, defined in pathological manifestations, using 179 MRL/lpr ×(MRL/lpr × C3H/lpr)F1 backcross mice and 266(MRL/lpa × C3H/lpr)F2 intercross mice, followed by precise mapping on chromosome 5 using 526 F2 intercross mice. As a result, the highest significant linkage of glomerulonephritis was mapped at the position of D5Mit115 on chromosome 5 in the same alias of osteopontin(OPN)gene, manifesting a dominant mode of susceptible inheritance of the MRL allele. To clarify the functional difference between the OPN allele of MRL and C3H strains in the developmental mechanisms of glomerulonephritis, we carried out a functional analysis of the polymorphic OPN derived from both strains, which were synthetically prepared in a Cell-Free System, using the short term co-culture system with splenocytes of MRL or C3H mice. MRL-OPN induced higher mRNA expression and production of IgG3 as well as cytokines including TNF-α and IL-1β than C3H-OPN.These findings suggest that an allelic polymorphism of OPN may play a critical role for the development of glomerulonephritis in MRL/lpr mice.