Genetic polymorphism of SLE

SLE基因多态性

• 批准号: 06404024
• 负责人: SHIRAI Toshikazu
• 金额: $ 19.84万
• 依托单位: Juntendo Univeristy
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 1994
• 资助国家: 日本
• 起止时间: 1994 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-06404024/
• 关键词: autoimmune disease; disease susceptibility gene; gene interaction; microsatellite markers; modifier gene; mutigenic disease; New Zealand mice; SLE; B-CLL; B1細胞; MHCハプロタイプ; 自己免疫; 遺伝子統御; 自己抗体; 抗リン脂質抗体症候群; 抗カルヂオリピン抗体; 抗血小板抗体; 血小板減少症; マイクロサテ

In SLE,a diversity of disease features in association with a wide spectrum of autoantibodies develops. There are subsets of patients with either antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune thrombocytopenia and/or even B-cell chronic lymphocytic leukemia (B-CLL). Because SLE is a multigenic disease, diversities of disease features in individual patients are thought to be due to different combinations of disease susceptibility genes contributing to each pathologic condition. This notion is consistent with findings observed in several genetically determined SLE-prone mouse models, in which particular autoantibodies are detected in one, but not in others. Studies indicated that, in addition to disease susceptibility alleles, disease modifiers are also involved in the development of each disease feature. To delineate the underlying genetic basis, we analyzed chromosomal segments containing loci contributing to each SLE feature, using NZB,NZW,(NZB x NZW) F1, (NZW x BXSB) F1, their backcross progeny, congenic strains, and transgenic mice. Results showed that each disease feature was independently controlled by different combinations of two to three, or more, major alleles, in which some were common and some were unique for different features. Gene interactions, in which some functioned in a coordinate manner and some, in an additive manner as a threshold liability model for the disease susceptibility, were suggested. There were several potentially important candidate genes, which may be relevant to each disease feature. We could identify several alleles which regulate aberrant proliferation and/or differentiation of B1, cells, precursors of both pathogenic autoantibody-producing cells and B-CLL.

在SLE中，与广泛的自身抗体相关的疾病特征的多样性发展。患者包括抗磷脂综合征、自身免疫性溶血性贫血、自身免疫性血小板减少症和/或B细胞慢性淋巴细胞白血病(B-CLL)。由于SLE是一种多基因疾病，个体患者疾病特征的多样性被认为是由于导致每种病理状态的不同疾病易感基因组合所致。这一概念与在几个遗传决定的SLE易感小鼠模型中观察到的结果是一致的，在这些模型中，在一个模型中检测到特定的自身抗体，而在其他模型中没有检测到。研究表明，除了疾病易感等位基因外，疾病修饰物也参与了每种疾病特征的发展。为了阐明潜在的遗传基础，我们利用NZB、NZW、(NZB×NZW)F1、(NZW×BXSB)F1、它们的回交后代、同源品系和转基因小鼠，分析了包含每个SLE特征的基因座的染色体片段。结果表明，各病害性状由2~3个或多个主效等位基因组成的不同组合独立控制，其中有些是常见的，有些是不同性状所特有的。基因交互作用，其中一些是协同作用，一些是相加作用，作为疾病易感性的阈值易感性模型，被提出。有几个潜在的重要候选基因，可能与每个疾病特征相关。我们可以鉴定出几个调控B1细胞异常增殖和/或分化的等位基因，B1细胞是致病自身抗体产生细胞和B-CLL的前体细胞。

项目成果

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Hirose, S.、Yan, K.、Abe, M.、Jiang, Y. 等人：“基因组 Fas 完整的自身免疫性疾病中用于产生自身抗体的前体 B 细胞不会受到 Fas 介导的免疫消除的影响。”