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因素有关 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 实验室已证明HLA-DQ基因相互作用具有很强的作用。 抗 Ro/SSA、抗 La/AAB 和类风湿因子自身抗体的产生 原发性干燥综合征中的抗 Ro/SSA 以及系统性狼疮中的抗 Ro/SSA HLA-DQ 杂合子患者的红斑狼疮率显着升高 等位基因 DQ1 和 DQ2。 由于 HLA-DQ 表面分子由两个 肽（Alpha 和 Beta），并且由于这两种肽都是多态性的， 可能产生具有独特抗原性的反式相关表面分子 特殊性。 这些分子的存在先前已被证实 已证实，但尚未发现针对它们的特异性免疫反应 以前在人类中已知。 我们将检验自身抗体的假设 原发性干燥综合征中的产生和系统性狼疮中的抗 Ro/SSA 由于 HLA-DQ 基因互补，红斑狼疮症状得到增强。 我们建议直接鉴定所涉及的基因。 基因探针用于 单个肽、DQAlpha、DQBeta 和 DRAlpha 将与 来自患者的限制性酶消化和 Southern 印迹基因组 DNA 原发性干燥综合征、系统性红斑狼疮和正常人。 将分析这些患者的家谱以制作单倍型 限制性片段长度多态性和 HLA 的命名 血清学。 可能的模型（尤其是基因互补）将是 测试了他们解释从以下来源获得的综合数据的能力 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。 即使这个分析确定了一个主要的 由于基因互补的作用，可能会有很多患者 其数据不符合明显的主效应。 的解释 将使用其他试剂寻求主要效应的例外情况。 单克隆抗体、HLA 反应性 T 细胞系和基因探针将 提出并用于确定贡献的关键结构 以确定它们在功能上是否与那些组件相似 占主要效应（现在在 DQ1/DQ2 杂合子中发现）。 这些额外的试剂将用于绘制这些影响 主要组织相容性复合体。 对于精心挑选的实例， 相关基因的可变区将被测序以使得 可能寻找分子结构中重要的相似之处。 这个 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中自身抗体的产生 红斑狼疮。 生成的试剂有望改善 诊断，或许还有治疗。

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.