Role of the transcription factor ARID3a in lupus

描述(由申请人提供)：这项研究的主要目标是确定转录因子ARID3a在系统性红斑狼疮患者子集中的过度表达是否是导致这种疾病的一个因素。我们之前的研究表明，小鼠ARID3a同源基因在B系细胞中的过度表达会导致B细胞耐受性的破坏。过度表达的转基因小鼠在四周大的时候会产生抗核抗原抗体(狼疮的一个特征)，在肾小球中积累免疫球蛋白沉积，并显示外周血B细胞亚群的数量变化。我们的初步数据表明，ARID3a在一大群狼疮患者中异常过度表达，但在年龄匹配的健康个体中不存在。我们假设，异常表达的患者可能构成了具有类似潜在缺陷的新的患者亚群。此外，我们假设ARID3a的过度表达促进了疾病的发展。提出了三个具体目标。首先，我们将确定ARID3a异常表达是某些患者的稳定特征，还是随着时间的推移药物治疗或免疫反应导致过度表达。其次，我们将确定ARID3a的异常表达如何影响B细胞功能，这可能直接与B细胞耐受性的破坏有关。最后，我们将确定导致ARID3a在这些细胞中异常表达的具体机制。这些数据将为指导未来的研究提供基础，以确定ARID3a如何促进自身免疫。根据特定症状对患者进行分组并了解导致狼疮的潜在机制的能力可能会导致更好的治疗方案。 公共卫生相关性：我们公布的数据表明，转录因子ARID3a/Bright在转基因小鼠B细胞中过度表达会导致自身免疫抗体的产生。初步的新数据表明，ARID3a在狼疮患者中有不适当的表达。这项研究的目的是确定不适当的ARID3a表达是否有助于狼疮的发病。

DESCRIPTION (provided by applicant): The goal primary of this study is to determine if over-expression of the transcription factor ARID3a in a subset of systemic lupus erythematosus patients is a contributing factor to this disease. We previously showed that over-expression of the mouse orthologue of ARID3a in B lineage cells results in breaches of B cell tolerance. The over-expressing transgenic mice produce anti-nuclear antigen antibodies (a defining characteristic of lupus) by four weeks of age, accumulate immunoglobulin deposits in kidney glomeruli and exhibit shifts in numbers of peripheral blood B cell subsets. Our preliminary data indicate that ARID3a is aberrantly over-expressed in a large subset of lupus patients, but not in healthy age-matched individuals. We hypothesize that patients with aberrant expression may constitute a new subgroup of patients with similar underlying defects. Furthermore, we hypothesize that ARID3a over-expression facilitates disease development. Three specific aims are proposed. First, we will determine if aberrant ARID3a expression is a stable characteristic of some patients, or if over-expression occurs as the result of drug treatment or immune response over time. Secondly, we will determine how aberrant ARID3a expression affects B cell functions which may pertain directly to breaches in B cell tolerance. Finally, we will identify the specific mechanisms which contribute to aberrant ARID3a expression in these cells. These data will provide the basis for directing future studies to determine how ARID3a contributes to autoimmunity. The ability to group patients by specific symptoms and to understand the underlying mechanisms which contribute to lupus could lead to better treatment regimens. PUBLIC HEALTH RELEVANCE: Our published data indicate that over-expression of the transcription factor ARID3a/Bright in transgenic mouse B cells results in production of autoimmune antibodies. Preliminary new data suggest that ARID3a is inappropriately expressed in a subset of lupus patients. The goal of this study is to determine if how inappropriate ARID3a expression contributes to lupus pathogenesis.