Genetic and Environmental Modifiers Of Autoimmune Disease

我们小组的主要重点是识别导致系统性自身免疫性疾病发展的基因和环境因素的特征。我们使用系统性红斑狼疮(SLE)的小鼠模型来确定某些分子途径和细胞相互作用在自发自身免疫病理中的必要性。此外，我们还分析了外部影响，如感染，在SLE进展中的作用。从这些研究中获得的新的机制洞察力可以指导未来治疗人类SLE患者的治疗策略。 我们之前曾将Ig G受体FcGammaRIIB缺陷的小鼠描述为公认的系统性红斑狼疮小鼠模型。对FcGammaRIIB缺陷系中SLE的其他遗传修饰物的鉴定使我们能够确定几个与抗病毒RNA传感器连锁的基因，包括TLR7、MDA5和MAVS，是自身免疫性疾病的易感因素。这一概念已经得到了多个研究小组的验证，这些小组使用小鼠模型和人类SLE患者。 我们最近发现线粒体抗病毒信号(MAVS)接头蛋白在抗原受体刺激的B细胞代谢适合性中的作用，从而在预防自身免疫中发挥作用。众所周知，MAVS是一种线粒体连接的信号适配器，用于检测病毒双链RNA和I型干扰素诱导剂。在缺乏干扰素的情况下，MAVS在B细胞受体刺激下游的作用被认识到，这提示了一条不依赖病毒感染的MAVS激活的新途径。 作为我们以环境因素为中心的研究的一部分，我们在SLE小鼠模型中研究了感染和自身免疫性疾病之间的相互作用。例如，我们关于疟疾对系统性红斑狼疮的影响的工作为终末期自身免疫性肾炎提供了新的见解。我们观察到，单一感染小鼠疟疾寄生虫对致死性自身免疫性肾小球肾炎有保护作用，同时保持系统高水平的自身反应性。最近的实验发现，在SLE小鼠模型中，寄生虫诱导的骨髓长期倾斜在终末期肾脏疾病中具有保护作用。

The main focus of our group is the identification of characterization of genes and environmental factors that contribute to the development of systemic autoimmune disease. We use mouse models of systemic lupus erythematosus (SLE) to determine the necessity of certain molecular pathways and cellular interactions in the spontaneous autoimmune pathology. In addition, we analyze the effect of external influences, such as infections, in the progression of SLE. New mechanistic insight obtained from these studies can guide future therapeutic strategies to treat SLE in human patients. We previously described mice deficient in the IgG receptor FcgammaRIIB as a well-established murine model for SLE. Characterization of other genetic modifiers of SLE in the FcgammaRIIB-deficient line allowed us to determine that several genes linked to anti-viral RNA sensors including TLR7, MDA5 and MAVS, were susceptibility factors for autoimmune disease. This concept has been validated by multiple groups that work with mouse models and human SLE patients. We recently uncovered a role for the mitochondrial antiviral signaling (MAVS) adaptor protein in the metabolic fitness of antigen-receptor stimulated B cells, with consequences in the prevention of autoimmunity. MAVS is well known as a mitochondrial-tethered signaling adaptor for sensing viral double-stranded RNA and type I interferon inducer. The role of MAVS downstream of B cell receptor stimulation was recognized in absence of interferon, suggesting a new pathway for MAVS activation that is independent of viral infection. As part of our investigation centered on environmental factors, we looked into interactions between infections and autoimmune disease in SLE mouse models. As an example, our work on the effect of malaria on SLE provided new insights into end-stage autoimmune nephritis. We observed that a single infection with a murine malaria parasite had a protective effect on lethal autoimmune glomerulonephritis while maintaining high levels of autoreactivity systemically. Recent experiments led to our finding of parasite-induced long-term skewing of the bone marrow with a protective effect in end-stage kidney disease in mouse models of SLE.