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

An MRL/Mp /lpr /lpr strain of mice(MRL/lpr)with deficit in Fas is a well-known model of autoimmunediseases包括nephritiswhile C3H/HeJ-lpr/lpr mice do not develop the diseases. We performed genome wide screeningof susceptibility loci to the development of glomerulonephritis，定义pathological manifestations，using 179 MRL/lpr ×（MRL/lpr × C3H/lpr）F1 backcross mice and 266(MRL/lpa × C3H/lpr)F2 intercrossmice, followed by precise mapping on chromosome 5using 526 F2 intercross mice. As a result，the highest significant linkage of glomerulonephritis was mapped at the position of D5Mit115 onchromosome 5 in the same alias of osteopontin(OPN)genemanifesting a dominant mode of susceptible inheritance of the MRL allele. To clarify the functionaldifference between the OPN allele of MRL and C3H strains in the developmental mechanisms ofglomerulonephritis,我们carried out a functional analysis of the polymorphic OPN derived from both strainswhich were synthetically prepared in a Cell-Free Systemusing the short term co-culture system with splenocytes of MRL or C3H mice. MRL- opn induced highermRNA表达式和产品的IgG3 as well as cytokines including TNF-α和IL-1β thanC3H-OPN. these findings suggest that an allelic polymorphism of OPN may play a critical role for thedevelopment 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.