HLA GENE COMPLEMENTATION IN PRIMARY SJOGREN'S AND LUPUS

自身免疫性疾病中自身抗体的产生与特定的 在主要组织相容性复合体中发现的等位基因或单倍型。我们的 实验室已经证明了人类白细胞抗原-DQ的基因交互作用很强。 抗Ro/SSA、抗La/AAB和类风湿因子自身抗体的产生 原发性干燥综合征患者和系统性红斑狼疮患者的抗Ro/SSA抗体 在人类白细胞抗原DQ杂合子的患者中，红斑病的发生率显著升高。 等位基因DQ1和DQ2。由于人类白细胞抗原-DQ表面分子由两个 多肽(Alpha和Beta)，由于这两种多肽都是多态的， 可能产生具有独特抗原性的反式关联的表面分子 具体细节。这些分子的存在已经在以前 已经证实，但还没有针对它们的免疫反应性 以前在人类中已知。我们将测试自身抗体的假设 原发性干燥综合征的发生与系统性红斑狼疮抗Ro/SSA抗体的关系 由于人类白细胞抗原-DQ的基因互补，红斑病得到了增强。 我们建议直接鉴定相关基因。人类基因组的基因探针 单肽、DQAlpha、DQBeta和DRAlpha将与 限制性内切酶酶切和Southern杂交检测患者基因组DNA 患有原发性干燥综合征、系统性红斑狼疮和正常人。 这些患者的家系将被分析以制作单倍型 限制性片段长度多态和人类白细胞抗原的设计 血清学。可能的模式(特别是基因互补)将是 测试它们解释从以下来源获得的组合数据的能力 自身抗体血清学、人类白细胞抗原数据和限制性片段长度 多态分型分析。即使这项分析确定了一个主要的 从基因互补的效果来看，很可能会有一些患者 其数据与明显的主效应不符。对这一事件的解释 将使用其他试剂寻找主要影响的例外情况。 单抗、人类白细胞抗原反应性T细胞株和基因探针将 引发并用于标识做出贡献的关键结构 组件以确定它们在功能上是否类似于 解释了主要影响(现在在DQ1/DQ2杂合子中发现)。 这些额外的试剂将用于在 主要组织相容性复合体。对于精心选择的实例， 有问题的基因的可变区将被测序，以使 可能在分子结构上寻找重要的相似之处。这 研究将使我们更接近自身免疫性疾病的机制 阐明影响诱导和/或的遗传因素 原发性干燥综合征和全身性干燥综合征自身抗体的产生 红斑狼疮。产生的试剂可能会有改进的希望 诊断，也许还有治疗。

Autoantibody production in autoimmune diseases is related to particular alleles or haplotypes found in the major histocompatibility complex. Our laboratory has demonstrated a strong effect of gene interaction of HLA-DQ. Autoantibody production of anti-Ro/SSA, anti-La/AAB and rheumatoid factor in primary Sjogren's syndrome, and of anti-Ro/SSA in systemic lupus erythematosus is dramatically higher in patients heterozygous at HLA-DQ for alleles DQ1 and DQ2. Since the HLA-DQ surface molecule is composed of two peptides (Alpha and Beta) and since both of these peptides are polymorphic, trans-associated surface molecules may result which have unique antigenic specificities. The existence of these molecules has been previously demonstrated, but no immune reactivity specific for them has been previously known in man. We will test the hypothesis that autoantibody production in primary Sjorgren's syndrome and anti-Ro/SSA in systemic lupus erythematosus are enhanced as a result of gene complementation at HLA-DQ. We propose to directly identify the genes involved. Gene probes for the individual peptides, DQAlpha, DQBeta and DRAlpha will be hybridized to the restriction enzyme digested and Southern blotted genomic DNA from patients with primary Sjogren's syndrome, systemic lupus erythematosus and normals. Pedigrees from these patients will be analyzed to make haplotype designation of the restriction fragment length polymorphisms and of HLA serology. The possible models (especially gene complementation) will be tested for their capacity to explain the combined data obtained from autoantibody serology, the HLA data and restriction fragment length polymorphism typing analysis. Even if this analysis identifies a major effect from gene complementation, there will likely be a number of patients whose data does not fit the apparent main effect. Explanations for the exceptions to the major effects will be sought using other reagents. Monoclonal antibodies, HLA responsive T cell lines and gene probes will be raised and used to identify the critical structures of the contributing components to determine whether they are functionally similar to those accounting for the major effect (now found in DQ1/DQ2 heterozygotes). These additional reagents will be used to map these effects within the major histocompatibility complex. For carefully selected instances, the variable regions of the genes in question will be sequenced to make possible a search for important similarities in molecular structure. This study will bring us closer to the mechanism of autoimmune disease by elucidating the genetic elements which influence induction and/or production of autoantibodies in primary Sjogren's syndrome and systemic lupus erythematosus. Reagents generated may hold promise for improved diagnosis and, perhaps, therapy.