ALLELIC POLYMORPHISM IN HLA-DRB REGULATORY REGION GENES

虽然特定的HLA II类抗原与 已知自身免疫性疾病已有一段时间， HLA连锁易感性的基础尚不清楚。 是否 这些易感性等位基因的差异调节也 导致疾病风险是一个重要的问题， 处理。 II类分子的定量差异 在细胞表面表达的蛋白质可以影响细胞的 此外，启动子变异可以改变免疫应答， 这些分子可能异常的组织特异性 表达。 我们假设等位基因特异性功能性 差异，由启动子中的核苷酸变异引起 特定DRB等位基因的区域，可能在 改变免疫反应，从而促进 与自身免疫性疾病相关的HLA II类等位基因。 我们 建议确定调控区的核苷酸序列 从一些疾病相关的HLA-DRB等位基因，并测试 它们在功能上用于相对启动子中的等位基因差异 强度，核蛋白的结合，由特定的 细胞因子和组织特异性。 这种示范 启动子区等位基因多态性揭示了 在启动正常和异常的免疫反应， 对引发自身免疫性疾病有重要意义。

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.