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

在全身性自身免疫性疾病中，SLE的肾脏表现尤为严重，严重影响患者的死亡率。目前尚无针对LN的特异性治疗药物获批；相反，它是用免疫抑制剂治疗的，这会引起各种意想不到的副作用。因此，迫切需要开发新的治疗方法。III型干扰素系统——紧挨着I型干扰素系统——可能就是这样一种方法：在模式识别受体被核酸激活后，两者都作为早期介质表达。这不仅发生在病毒感染中，也可能发生在自身免疫性疾病中——这是由SLE患者pbl中ANAs（抗核自身抗体）的强烈表达增强和所描述的干扰素特征所表明的。虽然I型ifn受体普遍表达，但III型ifn受体的表达似乎仅限于上皮细胞。因此，它们的影响可能会受到更多限制。这可能是LN治疗方法的一个优势，因为对传染病的易感性等不必要的副作用可以最小化。在初步研究中，我们观察到III型ifn受体在肾小管上皮细胞上的功能性表达。III型ifn可诱导TEC中促炎介质的表达，从而促进LN期间的慢性炎症。此外，我们可以观察到，在狼疮易感MRL Faslpr小鼠中，III型IFN的表达随着肾脏和次级淋巴器官LN疾病活动性的增加而加速，这与I型IFN的表达相关。在本项目中，我们旨在确定III型IFN信号在LN中与MRL Faslpr III型IFN受体KO小鼠的功能作用，并将其与I型IFN受体KO MRL Faslpr小鼠进行比较。每个IFNR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：我们的目标是在RNA和蛋白质水平上确定LN患者肾活检中III型IFN的表达。此外，我们想要确定III型ifn在体外肾TEC与肾浸润性免疫细胞通讯中的作用。不同的SLE表现（LN、盘状狼疮、心血管表现）可能受到I型和/或III型ifn以独特的方式影响——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ifn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.