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 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，using179MRL/lpr×(MRL/lpr×C3H/lpr)F1 backcross mice and 266(MRL/lpa×C3H/lpr)F2 intercross mice，followed by precise mapping on chromosome5 using526F2 intercross mice.As a result，the highest significant linkage of glomerulonephritis was mapped at the position of D5Mit115on chromosome5in 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 IgG3as well as cytokines including TNF-αand IL-1βthan 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.