Pathophysiological relevance of Type III in Systemic Lupus Erythematosus - significance and differences to Type I interferons

在系统性自身免疫性疾病中，系统性红斑狼疮的肾脏表现尤为严重，因为它对患者的死亡率有很大的影响。LN没有特定的治疗方法被批准；相反，它是用免疫抑制剂治疗的，这会导致各种不想要的副作用。因此，迫切需要开发新的治疗方法。III型干扰素系统--仅次于I型干扰素系统--可能是这样一种方法：两者都在模式识别受体被核酸激活后表达为早期介质。这不仅发生在病毒感染中，而且可能发生在自身免疫性疾病中-这从SLE患者PBL中ANAS(抗核自身抗体)的强烈增强和所描述的干扰素信号来表明。虽然I型干扰素受体普遍表达，但III型干扰素受体的表达似乎仅限于上皮细胞。因此，他们的影响力可能会受到更多限制。这可能是LN治疗方法的优势，因为可以最大限度地减少不必要的副作用，如对传染病的易感性。在初步研究中，我们观察了III型干扰素受体在肾小管上皮细胞上的功能表达。III型IFN可诱导TEC中促炎介质的表达，从而促进LN的慢性炎症反应。此外，我们可以观察到狼疮易感MRL Faslpr小鼠肾脏和次级淋巴器官中LN疾病活动性增加的III型干扰素的加速表达-与I型IFN的表达相关。在本项目中，我们旨在确定III型干扰素信号在MRL Faslpr III型干扰素受体KO小鼠LN中的功能作用，并与I型干扰素受体KO MRL Faslpr小鼠进行比较。每个IFNR基因敲除对细胞因子和趋化因子环境的不同影响将被确定。下一步是将在小鼠模型中获得的知识转移到人类SLE中：我们的目标是在RNA和蛋白质水平上确定LN患者肾活检组织中III型干扰素的表达。此外，我们希望在体外确定III型IFN在肾脏TEC与肾脏浸润性免疫细胞之间的通讯中所起的作用。系统性红斑狼疮的不同表现(LN、盘状狼疮、心血管表现)可能会受到I型和/或III型IFN的独特影响--确定哪种干扰素促进哪种表现是一个额外的目标。因此，III型干扰素应作为SLE的潜在疾病活动性标志物和一种新的治疗方法进行评估。

In the systemic autoimmune disease SLE is the renal manifestation especially serious, since it highly impacts the mortality of affected patients. No specific therapeutics are approved for LN; instead it is treated with immunosuppressors, that cause a variety of unwanted side effects. Hence, the development of new therapeutic approaches are urgent needed.The type III Interferon system – next to the type I Interferon system – could be such an approach: Both are expressed as early mediators after pattern recognition receptors are activated by nucleic acids. This occurs not only in viral infection but possibly during autoimmune diseases – this is indicated by the strongly enhanced expression of ANAs (Antinuclear Autoantibodies) and the described interferon signature in PBLs of SLE patients. While the type I IFN-receptor is expressed universally, the type III IFN-receptor expression seems to be restricted to epithelial cells. Hence, their influence could be more restricted. Which could be an advantage for a LN therapeutic approach, since unwanted side effects like susceptibility to infectious diseases could be minimized.In preliminary studies, we observed the functional expression of the type III IFN-receptor on renal tubular epithelial cells. Type III IFNs could induce the expression of proinflammatory mediators in TEC and thus promote the chronic inflammation during LN. Furthermore, we could observe an accelerated Type III IFN expression with increasing LN disease activity in kidneys and secondary lymphoid organs in lupus prone MRL Faslpr mice – correlating with the expression of type I IFNs.In this project we aim to determine the functional role of type III IFN signaling in LN with MRL Faslpr Type III IFN-receptor KO mice, and compare those to type I IFN-receptor KO MRL Faslpr mice. The distinct influence of each IFNR Knockout on the cytokine and chemokine milieu will be determined. The next step is to transfer the knowledge obtained in the murine model to human SLE: we aim to determine the type III IFN expression in kidney biopsies of LN patients on RNA and Protein level. Additionally, we want to determine the role of type III IFNs in the communication of renal TEC with kidney infiltrating immune cells in vitro. Diverse manifestations of SLE (LN, discoid Lupus, cardiovascular manifestation) could be affected by either type I and/or type III IFNs in a unique manner – to determine which interferon promotes which manifestation is an additional goal. Thus, type III IFNs shall be evaluated as potential disease activity markers for SLE and as a new therapeutic approach.