NIAMS: CORT - Genetic Dissection of SLE--From Mouse to Man

描述（由申请人提供）：UTSW-SLE-CORT 致力于将从基因简化小鼠模型中汲取的经验教训转化为人类 SLE。在过去的十年中，随着一系列单基因小鼠模型不断取代多基因狼疮小鼠模型，小鼠狼疮的研究得到了简化，这极大地简化了导致SLE致病机制的系统分析。重要的是，这些研究发现了至少两个导致狼疮的主要步骤，这两个步骤都是基因编码的。第一阶段的特点是存在抗核抗体，但不存在疾病，而第二阶段的特点是存在潜在致病性自身抗体和终末器官疾病。在小鼠模型中，第一阶段是 SLAM 家族基因多态性的结果，而第二阶段是由编码“高活性”促炎 DC 的基因位点驱动的。项目 1 侧重于使用小鼠模型研究两个阶段的分子基础，而项目 2-4 本质上是转化性的，侧重于识别人类 SLE 的相似阶段和致病机制。这些转化项目基于 UTSW-SLE-CORT Pis 在过去 2 年中进行的 3 个新颖观察：(1) 我们成功地识别出患有“早期”或“不完全”狼疮（或“ILE”）的个体，这些个体未能满足 SLE 诊断的最低要求，这让人想起一些患有“早期”狼疮的小鼠模型； (2) 我们已经确定，SLE 患者的某些种族亚群与特定 SLAM 家族基因，特别是 Ly108/SLAMF6 和 CD84 表现出很强的相关性，在小鼠中重现了观察结果； (3) 同样明显的是，人类狼疮 DC 或 IMF 处理的 DC 更能帮助 B 细胞产生抗体，这再次呼应了我们在小鼠中的发现。基于这些令人兴奋的线索，UTSWSLE-CORT 提议确定 SLAM 家族基因多态性和 DC 在人类 SLE 不同阶段驱动表型成熟的作用。除了揭示导致狼疮的致病机制外，这些研究还可能揭示最能预测人类 SLE 疾病进展的早期标志物。最后，基本项目 (I) 和拟议的 DC:B 细胞研究有可能发现疾病的关键分子介质，这可能为 SLE 的新治疗机会铺平道路。

DESCRIPTION (provided by applicant): The UTSW-SLE-CORT is focused on translating lessons learned from genetically simplified mouse models to human SLE. Over the past decade, the study of murine lupus has been simplified with the steady replacement of polygenic mouse models of lupus with a series of monogenic mouse models, which greatly simplify the systematic analysis of pathogenic mechanisms leading to SLE. Importantly, these studies have uncovered at least 2 major steps leading to lupus, both genetically encoded. Whereas the first stage is characterized by the presence of anti-nuclear antibodies but not disease, the second stage is marked by the presence of potentially pathogenic autoantibodies and end-organ disease. In the mouse models, the first stage arises as a consequence of polymorphisms in the SLAM family genes, whereas the second stage is driven by genetic loci that encode "hyperactive" pro-inflammatory DCs. Whereas Project 1 focuses on the molecular basis of the 2 stages using mouse models, Projects 2-4 are translational in nature, focusing on identifying similar stages and pathogenic mechanisms in human SLE. The translational Projects are based on 3 novel observations made by the UTSW-SLE-CORT Pis over the past 2 years: (1) We have succeeded in identifying individuals with "early" or "incomplete" lupus (or "ILE"), who fail to meet the minimum requirements for a diagnosis of SLE, reminiscent of some of the mouse models with "early" lupus; (2) We have already established that certain ethnic subsets of their SLE patients show strong association with particular SLAM family genes, notably Ly108/SLAMF6 and CD84, reproducing the observations in mice; (3) It is also evident that human lupus DCs or IMF-treated DCs are better at helping B-cells produce antibodies, again echoing our findings in mice. Based on these exciting leads, the UTSWSLE-CORT proposes to ascertain the role of SLAM family gene polymorphisms and DC help in driving phenotypic maturation in different stages of human SLE. Besides uncovering the pathogenic mechanisms leading to lupus, these studies may also uncover early markers that best predict disease progression in human SLE. Finally, the basic Project (I) and the proposed DC:B-cell studies have the potential to uncover key molecular mediators of disease, which could potentially pave the way towards novel therapeutic opportunities in SLE.