UV Light and Autoimmunity: A Role for Small Excised DNA Oligonucleotides

描述（由申请人提供）：在理解紫外线（UV）如何沉淀和加剧自身免疫性疾病红斑狼疮（LE）的症状方面存在根本性差距。这种知识的缺乏是一个重要的问题，因为它意味着需要对LE光敏性进行更多的机械洞察，并且代表了预测患者疾病结果严重程度的障碍。长期目标是更好地了解紫外线诱导的DNA损伤的修复如何控制人类疾病的发病机制。这个特殊的探索性建议的目的是检查如何小，切除，损伤的DNA寡核苷酸（sedDNA）核苷酸切除修复产品的影响异常炎症和免疫反应途径，定义LE，并确定皮肤LE患者是否开发自身抗体对蛋白质和sedDNA参与这些信号传导过程。中心假设是sedDNA与特定模式识别受体蛋白（PRR）的关联导致LE患者皮肤中自身免疫反应的过度刺激或放大。这一假设来源于初步数据和报告，即LE患者的皮肤和/或血液中存在较高水平的DNA结合PRR。这项研究的基本原理是，一旦了解了sedDNA和PRR在LE光敏性中的作用，就可以开发诊断和治疗LE的新策略。研究人员将通过追求以下三个具体目标来测试一种新的假设：1）识别与sedDNA相关的DNA敏感炎症和免疫反应信号蛋白（PRR）; 2）表征核苷酸切除修复和DNA敏感PRR基因在UV介导的炎症和免疫反应信号传导中的作用; 3）表征LE患者针对sedDNA和sedDNA结合蛋白的自身抗体。研究人员将使用新方法检测培养的人类细胞和小鼠皮肤中的sedDNA，以确定感知和响应sedDNA的特定炎症和免疫信号通路。然后将使用皮肤LE患者血清表征针对这些蛋白质和DNA的自身抗体反应性。这种方法是创新的，因为它为理解LE患者的炎症和免疫反应提供了一个新的和令人兴奋的范例。拟议的研究是重要的，因为它有望垂直推进和扩大紫外线如何有助于LE的皮肤和全身表现的理解。最终，这些知识有可能提高对LE患者光敏性的理解，并导致开发用于诊断、分类和治疗特定LE患者亚型的新工具。

DESCRIPTION (provided by applicant): There is a fundamental gap in understanding how ultraviolet (UV) light precipitates and exacerbates the symptoms of the autoimmune disorder lupus erythematosus (LE). This lack of knowledge is an important problem because it signifies a need for more mechanistic insight into LE photosensitivity and represents a barrier to predicting the severity of patient disease outcomes. The long-term goal is to better understand how the repair of UV-induced DNA damage controls human disease pathogenesis. The objective of this particular exploratory proposal is to examine how the small, excised, damage-containing DNA oligonucleotide (sedDNA) products of nucleotide excision repair impact the aberrant inflammatory and immune response pathways that define LE and to determine whether cutaneous LE patients develop autoantibodies against the proteins and sedDNAs that are involved in these signaling processes. The central hypothesis is that the association of sedDNAs with specific pattern recognition receptor proteins (PRRs) leads to the overstimulation or amplification of the autoimmune response in the skin of LE patients. This hypothesis has been derived from preliminary data and reports that a number of DNA-binding PRRs are present at higher levels in the skin and/or blood of LE patients. The rationale for the proposed research is that once the roles of sedDNAs and PRRs in LE photosensitivity is known, new strategies for diagnosing and treating LE may be developed. The investigators will test a novel hypothesis by pursuing the following three specific aims: 1) Identify the DNA-sensing inflammatory and immune response signaling proteins (PRRs) that associate with sedDNA; 2) Characterize the role of nucleotide excision repair and DNA-sensing PRR genes in UV-mediated inflammatory and immune response signaling; and 3) Characterize LE patient autoantibodies against sedDNAs and sedDNA-binding proteins. The investigators will use novel methods for detecting sedDNAs in cultured human cells and mouse skin to determine the specific inflammatory and immune signaling pathways that sense and respond to sedDNAs. Cutaneous LE patient sera will then be used to characterize autoantibody reactivity towards these proteins and DNAs. This approach is innovative because it provides a new and exciting paradigm for understanding inflammatory and immune responses in LE patients. The proposed research is significant because it is expected to vertically advance and expand understanding of how UV contributes to the cutaneous and systemic manifestation of LE. Ultimately, this knowledge has the potential to improve the understanding of LE patient photosensitivity and lead to the development of new tools for diagnosing, classifying, and treating specific LE patient subtypes.