期刊
JOURNAL OF IMMUNOLOGY
卷 190, 期 5, 页码 2129-2137出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1202196
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资金
- Genome Network Project of the Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health and Welfare of Japan
- Grants-in-Aid for Scientific Research [23590325, 21221004, 25460496] Funding Source: KAKEN
Systemic lupus erythematosus is considered to be under the control of polygenic inheritance, developing according to the cumulative effects of susceptibility genes with polymorphic alleles; however, the mechanisms underlying the roles of poly-genes based on functional and pathological genomics remain uncharacterized. In this study, we substantiate that a CD72 polymorphism in the membrane-distal extracellular domain impacts on both the development of glomerulonephritis and vasculitis in a lupus model strain of mice, MRL/MpJ-Fas(lpr), and the reactivity of BCR signal stimulation. We generated mice carrying a bacterial artificial chromosome transgene originating from C57BL/6 (B6) mice that contains the Cd72(b) locus (Cd72(B6) transgenic [tg]) or the modified Cd72(b) locus with an MRL-derived Cd72(c) allele at the polymorphic region corresponding to the membrane-distal extracellular domain (Cd72(B6)/MRL tg). Cd72(B6) tg mice, but not Cd72(B6)/MRL tg mice, showed a significant reduction in mortality following a marked improvement of disease associated with decreased serum levels of IgG3 and anti-dsDNA Abs. The number of splenic CD4(-)CD8(-) T cells in Cd72(B6) tg mice was decreased significantly in association with a reduced response to B cell receptor signaling. These results indicate that the Cd72 polymorphism affects susceptibility to lupus phenotypes and that novel functional rescue by a bacterial artificial chromosome transgenesis is an efficient approach with wide applications for conducting a genomic analysis of polygene diseases. The Journal of Immunology, 2013, 190: 2129-2137.
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