TY - JOUR
T1 - Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice
AU - Miyazaki, Tatsuhiko
AU - Ono, Masao
AU - Qu, Wei Min
AU - Zhang, Ming Cai
AU - Mori, Shiro
AU - Nakatsuru, Shuichi
AU - Nakamura, Yusuke
AU - Sawasaki, Tatsuya
AU - Endo, Yaeta
AU - Nose, Masato
PY - 2005/5
Y1 - 2005/5
N2 - Potentially, autoimmune diseases develop from a combination of multiple genes with allelic polymorphisms. An MRL/Mp-Faslpr/lpr (MRL/lpr) strain of mice develops autoimmune diseases, including lupus nephritis, but another lpr strain, C3H/HeJ-Faslpr/lpr (C3H/lpr) does not. This indicates that MRL polymorphic genes are involved in the development of the diseases. By quantitative trait loci (QTL) analysis using 527 of the (MRL/lpr × C3H/lpr)F2 mice, we identified a novel locus for susceptibility to lupus nephritis at map position D5Mit115 on chromosome 5, the same alias of the osteopontin (Opn) gene (LOD score = 4.0), susceptible in the MRL allele. In functional analyses of the MRL and C3H Opn alleles using synthetic osteopontin (OPN) made with a new method "cell-free system" with wheat germ ribosomes, the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-α, IL-1β and IFN-γ in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis.
AB - Potentially, autoimmune diseases develop from a combination of multiple genes with allelic polymorphisms. An MRL/Mp-Faslpr/lpr (MRL/lpr) strain of mice develops autoimmune diseases, including lupus nephritis, but another lpr strain, C3H/HeJ-Faslpr/lpr (C3H/lpr) does not. This indicates that MRL polymorphic genes are involved in the development of the diseases. By quantitative trait loci (QTL) analysis using 527 of the (MRL/lpr × C3H/lpr)F2 mice, we identified a novel locus for susceptibility to lupus nephritis at map position D5Mit115 on chromosome 5, the same alias of the osteopontin (Opn) gene (LOD score = 4.0), susceptible in the MRL allele. In functional analyses of the MRL and C3H Opn alleles using synthetic osteopontin (OPN) made with a new method "cell-free system" with wheat germ ribosomes, the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-α, IL-1β and IFN-γ in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis.
KW - Cell-free protein synthesis
KW - Glomerulonephritus
KW - Pathogenomics
KW - Polymorphic proteins
KW - QTL analysis
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U2 - 10.1002/eji.200425672
DO - 10.1002/eji.200425672
M3 - Article
C2 - 15832294
AN - SCOPUS:21044458103
SN - 0014-2980
VL - 35
SP - 1510
EP - 1520
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 5
ER -