Studies of autoimmune disease using mice with genetic recombination

使用基因重组小鼠研究自身免疫性疾病

• 批准号: 62480144
• 负责人: SHIRAI Toshikazu
• 金额: $ 3.97万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1987
• 资助国家: 日本
• 起止时间: 1987 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-62480144/
• 关键词: Autoimmunity; SLE; MHC; TCR; congenic mouse; transgenic mouse; New Zealand mouse; New Aealandマウス; 全身性エリテマト-デス; Transgenicマウス; New Zealandマウス; 全身性エリテマトーデス; クラスII抗原; コンジェニックマウス; トランスジェニックマウス; 自己免疫遺伝子

The multi-gene effect is responsible for the development of severe autoimmune disease in (NZB X NZW)Fl mice, resembling human systemic lupus erythematosus. Using H-2 congenic mouse strains, we demonstrated that the beterozygosity of the H-2^d from NZB and H-2^z from NZW mouse is required for the development of IgG anti-DNA antibodies and severe lupus nephritis in these mice, and have proposed that the Fl unique hybrid class ll molecules may act as a restriction element. This idea was supported by our finding of progeny studies in which a locus or a cluster of loci linked to T cell receptor beta chain gene complex of the NZW strain in combination with H-2^d/H-2^Z heterozygosity is associated with the production of IgG anti-DNA antibodies in these mice. Together with our previous finding of the strict CD4^+ T cell dependency of IgG anti-DNA antibody production in (NZB X NZW)Fl mice, it appears that the interaction between the unique structures of the T cell receptors and the Fl unique hy … More brid class II molecules is preferable for IgG anti-DNA antibody synthesis. We then analyzed the polymorphism of class II genes of NZB and NZW strains by the nucleotide sequence analysis, and found that NZW(H-2^z) Ebeta is identical to that of BlOPL(H-2^u) except for two N-terminal two amino acid differences (Arg^1 Gly^2 for Ebeta^u and Val^1 Arg^2 for Ebeta^z). The second exon sequences of NZW Abeta, Aalpha, Ealpha genes were shown to be identical to those of H-2^u. MHC class II polymorphism of NZB mice appeared to be identical to that of Balb/c mice(H-2^d). Analysis suggested that unique polymorphism in Ealpha alpha 1 domain of NZW mice which is so far found only in u and z haplotypes may contribute to the formation of Fl unique hybrid E molecule which should be formed in H-2^d/H-2^z heterozygosity. To investigate the possible roles of these Fl unique hybrid class II molecule on autoimmuno disease of (NZB X NZW) Fl mice. studies are under way using several strains of class II transgenic. H-2 congenic mice. Less

多基因效应导致（NZB X NZW）F1小鼠中严重自身免疫性疾病的发展，类似于人类系统性红斑狼疮。利用H-2同源小鼠品系，我们证明了来自NZB的H-2 ^d和来自NZW小鼠的H-2 ^z的杂合性是这些小鼠中IgG抗DNA抗体和严重狼疮肾炎的发展所必需的，并且提出了F1独特的杂交II类分子可能充当限制性元件。这一想法得到了我们后代研究结果的支持，在这些研究中，与NZW品系的T细胞受体β链基因复合物连锁的一个基因座或一组基因座与H-2 ^d/H-2 ^Z杂合性结合与这些小鼠中IgG抗DNA抗体的产生相关。结合我们先前在（NZB X NZW）F1小鼠中IgG抗DNA抗体产生的严格的CD 4 ^+ T细胞依赖性的发现，似乎T细胞受体的独特结构与F1独特的免疫调节因子之间的相互作用， ...更多信息 bridII类分子优选用于IgG抗DNA抗体合成。我们随后通过核苷酸序列分析对NZB和NZW株II类基因的多态性进行了分析，发现NZW（H-2^z）Ebeta与BlOPL（H-2^u）的Ebeta除了N端两个氨基酸的差异（Ebeta^u的Arg^1 Gly^2和Ebeta^z的Val^1 Arg^2）之外是相同的。NZW Abeta、Aalpha、Ealpha基因的第二外显子序列与H-2 ^u的第二外显子序列相同。NZB小鼠与Balb/c小鼠（H-2^d）的MHC II类基因多态性相似。分析表明，NZW小鼠Ealpha α 1结构域的独特多态性（迄今为止仅在u和z单倍型中发现）可能有助于F1独特杂合E分子的形成，该杂合E分子应在H-2^d/H-2^z杂合性中形成。研究这些F1独特的杂合II类分子在（NZB X NZW）F1小鼠自身免疫病中的可能作用。正在使用几种II类转基因菌株进行研究。H-2同源小鼠。少

项目成果

Shirai,T.: Proceeding of the 6th Seapal Congress of Rheumatology., Proceeding of the 6th Seapal Congress of Rheumatology.,

Shirai,T.：第六届 Seapal 风湿病学大会论文集。，第六届 Seapal 风湿病学大会论文集。，

Hirose,S.,Ogawa,S.,Nishimura,H.,Hashimoto,H.& Shirai,T.: "Association of HLA-DR2/DR4 heterozygosity with systemic lupuserythematosus in Japanese patients." J.Rheumatol.14. 1489-1492 (1988)

广濑 S.、小川 S.、西村 H.、桥本 H.

Shirai,T.,Hirose,S.,Okada,T.& Nishimura,H.: "Genetically Based Immunological Disorders in Inbred Mice" CRC Press,Inc.(Eds.Rihova,E.B,et al.),

白井 T.、广濑 S.、冈田 T.

Shirai,T.: "Genetic background of autoimmunity." proceeding of the 6th seapal congress of rheumatology(in press.

Shirai,T.：“自身免疫的遗传背景。”

Okada,T.,Abe,M.,Takiura,F.,Hirose,S,&Shirai,T.: "Distinct surface phenotypes of B cells responsible for spontaneous production of IgM and IgG anti-DNA antibodies in autoimmune-prone NZB X NEW F1 mice." Autoimmunity(in press).

冈田 T.、阿部 M.、泷浦 F.、广濑 S、