HLA GENE COMPLEMENTATION IN PRIMARY SJOGREN'S AND LUPUS

原发性干燥病和狼疮中的 HLA 基因互补

• 批准号: 3137909
• 负责人: Courtney Montgomery
• 金额: $ 13.08万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1990-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3137909
• 关键词: Sjogren's syndrome; alleles; autoimmune disorder; endonuclease; genetic regulation; genome; haploidy; heterozygote; laboratory mouse; major histocompatibility complex; monoclonal antibody; systemic lupus erythematosus

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.

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 实验室已经证明了HLA-DQ的基因相互作用的强烈效果。 抗Ro/SSA、抗La/AAB和类风湿因子自身抗体的产生 在原发性干燥综合征中，以及在系统性狼疮中抗Ro/SSA 在HLA-DQ杂合子患者中， 等位基因DQ 1和DQ 2。 由于HLA-DQ表面分子由两个 肽（α和β），并且由于这两种肽都是多态的， 可产生反式相关的表面分子，其具有独特的抗原性， 特殊性 这些分子的存在以前一直是 证明，但没有特异性的免疫反应， 我们将检验自身抗体 原发性干燥综合征和系统性狼疮中抗Ro/SSA的产生 红斑狼疮是由于HLA-DQ的基因互补而增强的。 我们建议直接鉴定相关基因。 基因探针 单独的肽，DQAlpha、DQBeta和DRAlpha将杂交到 限制性酶消化并Southern印迹患者基因组DNA 原发性干燥综合征系统性红斑狼疮和正常人 将对这些患者的家系进行分析， 限制性片段长度多态性和HLA的命名 血清学 可能的模型（特别是基因互补）将是 测试他们的能力，以解释从 自身抗体血清学、HLA数据和限制性片段长度 多态性分型分析 即使这一分析确定了一个主要的 由于基因互补的影响，可能会有许多患者 其数据不符合明显的主效应。 的解释 将使用其它试剂来寻找主要效应的例外。 单克隆抗体、HLA反应性T细胞系和基因探针将被用于 提出并用于确定关键结构的贡献 组件，以确定它们是否在功能上类似于 解释了主要效应（现在在DQ 1/DQ 2杂合子中发现）。 这些额外的试剂将被用于绘制这些影响， 主要组织相容性复合体 对于精心选择的实例， 基因的可变区将被测序， 可能是寻找分子结构中重要的相似性。 这 这项研究将使我们更接近自身免疫性疾病的机制， 阐明影响诱导的遗传因素和/或 原发性干燥综合征和全身性干燥综合征中自身抗体的产生 红斑狼疮 生成的试剂可能有望改善 诊断，也许，治疗。