Role of the transcription factor ARID3a in lupus

描述（由申请人提供）：本研究的主要目的是确定转录因子ARID3a在系统性红斑狼疮患者亚群中的过度表达是否是该疾病的促成因素。我们之前的研究表明，在B系细胞中过度表达ARID3a的小鼠同源物会导致B细胞耐受性的破坏。过表达的转基因小鼠在4周龄时产生抗核抗原抗体（狼疮的一个决定性特征），在肾小球中积累免疫球蛋白沉积，外周血B细胞亚群数量发生变化。我们的初步数据表明，ARID3a在很大一部分狼疮患者中异常过表达，但在年龄匹配的健康个体中却没有。我们假设，异常表达的患者可能构成了一个新的亚组患者相似的潜在缺陷。此外，我们假设ARID3a的过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的异常表达是否是某些患者的稳定特征，或者过度表达是否是药物治疗或长期免疫反应的结果。其次，我们将确定异常ARID3a表达如何影响B细胞功能，这可能与B细胞耐受性的破坏直接相关。最后，我们将确定导致这些细胞中ARID3a异常表达的具体机制。这些数据将为指导未来研究确定ARID3a如何促进自身免疫提供基础。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，可能会导致更好的治疗方案。

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.