MURINE MODELS OF GENERALIZED AUTOIMMUNITY

广义自身免疫的小鼠模型

• 批准号: 3155993
• 负责人: Argyrios N Theofilopoulos
• 金额: $ 30.63万
• 依托单位: SCRIPPS CLINIC AND RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1991-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3155993
• 关键词: autoimmune disorder; disease /disorder model; hybridomas; immunoglobulin G; immunoglobulin M; interleukin 2; laboratory mouse; orphan disease /drug; rheumatoid arthritis; rheumatoid factor; suppressor T lymphocyte; systemic lupus erythematosus; thymectomy

Mice with spontaneous lupus erythematosus- and rheumatoid arthritis-like manifestations are characterized by B cell hyperactivity, hypergammaglobulinemia and autoantibodies against a variety of self-antigens, particularly nuclear antigens and IgG. These autoantibodies appear to be central to disease, forming immune complexes which damage various organs. This proposal focuses on defining, at the clonal level, the molecular generation and structure of these effector molecules. Libraries of monoclonal autoantibody-producing hybridomas will be developed from different genetic background mice with spontaneous lupus/arthritis, and mice with experimentally-induced autoantibody production. The libraries will be screened with nucleic acid probes to define the usage patterns of VH-VL, gene families, joining (J), and complementarity-determining region (CDR) elements. Correlations with autoantibody isotype, antigenic specificity, strain of origin and means of induction will be made. mRNAs encoding heavy (H) and light (L) chains of selected monoclonal autoantibodies and the germline V genes from which they derive will be molecularly cloned, and complete nucleotide sequences of VH-DH-JH and VL-JL elements determined to define the genetic elements encoding their production, their relation to the respective germline elements and the involvement of somatic mutation in autoantibody generation. The contribution of germline genes to autoantibody specificity will be further examined by transfecting cells with functionally-rearranged germline and/or specifically mutagenized V genes, and assaying the expressed Ig products for autoantibody activity. Anti--idiotypic reagents against synthetic peptides from the autoantibodies' CDRs and molecular V region-specific probes will be prepared and used to define the extent of the autoantibody repertoire and the preponderance of certain idiotypes in sera and afflicted tissues, and thus the relationship of autoantibody structure with pathogenicity. These studies at the clonal level will allow definitive conclusions on the relationship of autoantibody structure to pathogenicity, their origin and regulation, and clarify the role of germline and somatic diversification mechanisms in autoimmune pathogenesis.

带有狼疮的小鼠红斑肿瘤和类风湿关节炎 表现的特征是B细胞多动， 高γ-球蛋白血症和自身抗体针对多种 自我抗原，尤其是核抗原和IgG。 这些自身抗体 似乎是疾病的核心，形成损害的免疫复合物 各种器官。 该提案的重点是在克隆级别定义 这些效应分子的分子产生和结构。 将开发单克隆自身抗体的库库。 来自自发狼疮/关节炎的不同遗传背景小鼠， 和具有实验诱导的自身抗体产生的小鼠。 这 库将用核酸探针筛选以定义使用情况 VH-VL的模式，基因家族，加入（J）和 互补性区域（CDR）元素。 与 自身抗体同种型，抗原特异性，起源应力和平均值 将进行归纳。 编码重（H）和光（L）链的mRNA 选定的单克隆自身抗体和它们的种系V基因 衍生将被分子克隆，并完整的核苷酸序列 VH-DH-JH和VL-JL元素确定定义遗传元件 编码他们的生产，与各自种系的关系 元素和体突变参与自身抗体 一代。 种系基因对自身抗体特异性的贡献 将通过功能重新培训转染细胞来进一步检查 种系和/或特定诱变的V基因，并分析 表达用于自身抗体活性的IG产物。 抗 - IDiotypic试剂 反对自身抗体的CDR和分子V的合成肽 将准备区域特异性探针，并用于定义 自身抗体曲目和某些白痴的优势 血清和受苦的组织，因此自身抗体的关系 致病性的结构。 这些在克隆层的研究将允许 关于自身抗体结构与 致病性，起源和调节，并阐明 自身免疫发病机理中的生殖线和躯体多元化机制。