PATHOGENESIS OF AUTOIMMUNITY IN MICE WITH SLE-LIKE ILLNESS

患有系统性红斑狼疮样疾病的小鼠自身免疫的发病机制

• 批准号: 3792211
• 负责人: A D STEINBERG
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3792211
• 关键词: B lymphocyte; DNA binding protein; Retroviridae; autoimmune disorder; bone marrow; cellular immunity; disease /disorder model; gel mobility shift assay; gene expression; genetic regulatory element; genetic strain; hematopoietic stem cells; immunogenetics; immunoglobulin M; laboratory mouse; leukocyte activation /transformation; lymphocyte proliferation; molecular pathology; nucleic acid probes; systemic lupus erythematosus; thymus

IN lupus-prone strains of mice, bone marrow derived pluripotent stem cells and/or their immediate progeny demonstrate excessive proliferation. They have increased numbers of both endogenous and exogenous stem cell derived B cell production of IgM and anti-DNA relative to other strains. The results were confirmed and extended using sorter purified stem cells. In addition, such sorter purified stem cells transfer the NZB phenotype to normal mice. These studies suggest a fundamental abnormality in stem cell activity. Retrovirus studies demonstrate excess Mpmv RNA in thymuses of lupus- prone mice. The abnormality is transferable with bone marrow stem cells. The basis for this abnormal expression has been studied. First, a genomic library from NZB mice was probed with Mpmv specific probes and a full-length clone isolated. The LTR was sequenced, demonstrating a mutation in a negative regulatory region. Gel retardation studies confirm that the mutation alters binding of a regulatory DNA binding protein.

在狼疮易感小鼠品系中，骨髓来源的多能干细胞 细胞和/或它们的直接后代表现出过量的 增殖他们增加了内源性和 外源性干细胞来源的B细胞产生IgM和抗DNA 相对于其他菌株。结果得到证实，并扩大使用 分选纯化的干细胞。此外，这种分选纯化的干细胞 将NZB表型转移到正常小鼠。这些研究表明， 干细胞活性的根本异常。 逆转录病毒研究表明狼疮患者胸腺中存在过量的Mpmv RNA- 俯卧的老鼠骨髓干细胞的异常是可转移的。 对这种异常表达的基础进行了研究。一是 来自NZB小鼠的基因组文库用Mpmv特异性探针探测， 分离全长克隆。对LTR进行了测序，证明了LTR是一个 负调控区的突变。凝胶阻滞研究 证实突变改变了调节DNA结合的结合， 蛋白