ALLELIC POLYMORPHISM IN HLA-DRB REGULATORY REGION GENES

HLA-DRB 调控区基因的等位基因多态性

• 批准号: 3791623
• 负责人: BARBARA S NAPOM
• 金额: --
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 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/3791623
• 关键词: DNA footprinting; MHC class II antigen; binding proteins; cytokine; genetic polymorphism; genetic promoter element; genetic transcription; histocompatibility gene; human genetic material tag; human tissue; immunogenetics; nuclear runoff assay; nucleic acid sequence; polymerase chain reaction; regulatory gene; rheumatoid arthritis; site directed mutagenesis

While the association of particular HLA Class II antigens with autoimmune diseases has been known for some time, the molecular basis for HLA-linked susceptibility is unknown. Whether the differential regulation of these susceptibility alleles also contributes to disease risk ia an important issue that has not been addressed. Quantitative differences in Class II molecules expressed on the cell surface can influence the intensity of the immune response, and in addition, promoter variation can alter the specificity of tissues in which these molecules might be aberrantly expressed. We hypothesize that allele-specific functional differences, resulting from nucleotide variations in the promoter regions of particular DRB alleles, may play a crucial role in altering the immune response and thus contribute to the association of specific HLA Class II alleles with autoimmune disease. We propose to determine the nucleotide sequence of regulatory regions from a number of disease-associated HLA-DRB alleles, and to test them functionally for allelic differences in relative promoter strength, binding of nuclear proteins, inducibility by particular cytokines, and tissue specificity. The demonstration of such promoter region allelic polymorphism sheds light on a critical step in the initiation of normal and abnormal immune responses, and has important implications for the triggering of autoimmune diseases.

而特定的人类白细胞抗原II类抗原与 自体免疫性疾病已经知道一段时间了，分子 人类白细胞抗原相关易感性的基础尚不清楚。无论是 这些易感等位基因的差异调节也 增加疾病风险是一个重要的问题，但 地址。第II类分子的数量差异 在细胞表面的表达会影响细胞内 免疫反应，此外，启动子的变异可以改变 这些分子可能发生异常的组织的特异性 表达。我们假设等位基因特异的功能 差异，由启动子中的核苷酸变化引起 特定DRB等位基因的区域可能在 改变免疫反应，从而促进这种联系 自身免疫性疾病的特定的人类白细胞抗原II类等位基因。我们 建议确定调节区的核苷酸序列 从一些与疾病相关的HLA-DRB等位基因中，并测试 它们在相对启动子等位基因差异中的作用 核蛋白的结合强度，特别是诱导性 细胞因子和组织特异性。证明了这一点 启动子区域等位基因多态揭示关键一步 在正常和异常免疫反应的启动中，并具有 对自身免疫性疾病的触发具有重要意义。