2002 Fiscal Year Final Research Report Summary
Establishment of knock-in mice for functional analysis of FcyRIIB regulatory region polymorphism
| Project/Area Number |
13680916
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Laboratory animal science
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| Research Institution | Juntendo University |
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Principal Investigator |
YI Jiang Juntendo Univ., Dept. Pathol., Instructor, 医学部, 助手 (50276466)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Kazuhiro Juntendo Univ., Dept. Pathol., Instructor, 医学部, 助手 (10327835)
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| Project Period (FY) |
2001 – 2002
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| Keywords | systemic lupus erythematosus / susceptibility gene / FcyRIIB1 molecule / hyper- IgG / linkage analysis / promoter region polymorphism / AP-4 / germinal center B cells |
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| Research Abstract |
FcyRIIB1 serves as negative feedback regulator for BCR-elicited activation of B cells, thus, any impaired FcyRIIB1 function may possibly be related to aberrant B cell activation. We earlier found deletion polymorphism in the Fcgr2b promoter region among mouse strains, in which systemic autoimmune disease-prone NZB, BXSB and MRL. but not NZW, BALB/c and C57BL/6 mice, have two identical deletion sites, consisting of 13 and 3 nucleotides. Here we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcyRIIB1 expression levels in germinal center (GC) B cells and up-regulates IgG antibody responses. We did luciferase reporter assays to determine if NZB-type deletion polymorphism affects transcriptional regulation of Fcgr2b gene. While NZW-derived segments from position -302 to +585 of Fcgr2b upstream region produced significant levels of luciferase activities, only a limited activity was detected in the NZB-derived sequence. Electrophoretic morbility shift assay and Southwestern analysis revealed that defect in transcription activity in the NZB-derived segment is likely due to absence of trans-activation by AP-4, which binds to the polymorphic 13 nucleotide deletion site. Our data imply that because of the deficient AP-4 binding, the NZB-type Fcgr2b allele polymorphism results in up-regulation of IgG antibody responses through down-regulation of FcyRIIB1 expression levels iu GC B cells, and that such polymorphism may possibly form the basis of autoimmune susceptibility in combination with other background contributing genes.
We are on the way to establish homologous recombination mouse strain for Fcgr2b promoter region polymorphism using 1 29-derived ES cell lines and have obtained two positive clones.
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[Publications] Miura-Shimura Y, Nakamura K, Ohtsuji M, Tomita H, Jiang Y, Abe M, Zhang D, Hamano Y, Tsuda H, Hashimoto H, Nishimura H, Taki S, Shirai T, Hirose S: "Clq regulatory region polymorphism down-regulating marine Clq protein levels with linkage to lupus nephritis"J Immunol. 169. 1334-1339 (2002)
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「研究成果報告書概要(欧文)」より
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[Publications] Xie Y, Nakamura K, Abe M, Li N, Wen X-S, Jiang Y, Zhang D, Tsurui H, Matsuoka S, Hamano Y, Fujii H, Ono M, Takai T, Shimokawa T, Ra C, Shirai T, Hirose S: "Transeriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses"J Immunol. 169. 4340-4346 (2002)
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「研究成果報告書概要(欧文)」より
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