Disturbance of the Interleukin 1 (IL-1)/type 1 interferon/IL-18 balance as possible driver of cytokine storm and cytopenia in Macrophage Activation Syndrome

系统性幼年特发性关节炎（systemic juvenile idiopathic arthritis，sJIA）是一种严重的儿童关节炎，其特征在于高热、皮疹、淋巴结病和关节炎的发作。许多未知的遗传决定因素，可能与尚未确定的环境因素相结合，导致疾病的发生和进展。sJIA中的炎症的特征是在细胞应激或不受控制的细胞死亡过程中释放的分子（损伤相关模式分子，DAMP）以及白细胞介素1家族的细胞因子，即IL-1b和IL-18。确诊后，sJIA患者经常接受类固醇或靶向IL-1b的治疗，但这些治疗的成功率目前尚无法预测。无论成功的治疗管理，sJIA患者是在建立巨噬细胞活化综合征（MAS）的一个严重的，潜在的致命的并发症的疾病的持续风险。大约10%的sJIA患者患有需要重症医学护理的全面MAS。如今，目前对导致MAS的机制过程的了解表明IL-18发挥着重要作用。重要的是，我们最近鉴定了1型干扰素，其主要在病毒防御过程中产生，以关键地调节人IL-18表达。这符合MAS发作与病毒感染相关的临床经验。它还强调了1型干扰素在表达调节方面的根本差异，否则高度相关的炎性细胞因子IL-1和IL-18。虽然IFN α/B信号抑制IL-1 B的表达和信号，我们证明，它促进IL-18的生产。事实上，这种相互作用对于平衡抗细菌与抗病毒免疫是至关重要的，因为IFNa/B抵消IL-1表达和信号传导，但控制炎性单核细胞的募集和IL-18表达。反过来，IL-1信号传导可以限制IFN α/B表达。在本项目中，我们现在的目标是a）了解DAMP信号传导对1型干扰素和IL-18表达的贡献，以及B）研究抗IL-1治疗（其是sJIA的标准治疗）是否实际上可以使IL-1b-T1 IFN反调节不稳定，这可能导致过度的IL-18表达，从而可能易患炎症过度和MAS。总的来说，本文产生的数据将增加我们对炎症环境与特定抗炎药物一起如何可能易患MAS以及sJIA患者中1型干扰素特征的监测是否可以支持炎症过度的预测的理解。我们的数据可能进一步有助于确定在其他方面非常成功的IL-1治疗的警告，在特定情况下（遗传易感性，感染触发因素的性质）实际上可能构成风险因素。

Systemic juvenile idiopathic arthritis (sJIA) is a severe form of childhood arthritis, that is characterized by episodes of high-spiking fever, rash, lymphadenopathy and arthritis. Many, yet unknown genetic determinants, likely in combination with still un-identified environmental factors contribute to disease onset and progression. Inflammation in sJIA is hallmarked by molecules released in course of cell stress or uncontrolled cell death (Damage associated pattern molecules, DAMPs) as well as cytokines of the interleukin 1 family, namely IL-1b and IL-18. Following diagnosis, sJIA patients are frequently treated with steroids or therapies targeting IL-1b but success of these treatments is currently unpredictable. Regardless of successful therapeutic mangment, sJIA patients are at the continous risk to establish Macrophage Activation Syndrome (MAS) a severe, potentially fatal complication of the disease. Full-blown MAS requiring intensive medical care affects approximately 10% of sJIA patients. Today, current understanding of the mechanistic processes leading to MAS suggest an important role for IL-18. Importantly we recently identified type 1 interferons, which are mainly produced in course of viral defense, to critically modulate human IL-18 expression. This fits the clinical experience of episodes of MAS to associate with viral infection. It also highlights a fundamental difference of type 1 interferons in expression-regulation of the otherwise highly related inflammatory cytokines IL-1 and IL-18. While IFNa/b signaling restrains IL-1b expression and signaling, we demonstrate that it promotes IL-18 production. In fact, this interplay is crucial for balancing anti-bacterial versus anti-viral immunity in that IFNa/b counteracts IL-1 expression and signaling, but controls recruitment of inflammatory monocytes and IL-18 expression. In turn, IL-1 signaling can limit IFNa/b expression. In the present project we now aim to a) understand the contribution of DAMP-signaling to type 1 interferon and IL-18 expression and b) investigate whether anti-IL-1 therapies, which are standard-of-care in sJIA, can in fact destabilize the IL-1b-T1IFN counter-regulation, which may than result in excessive IL-18 expression and thus can predispose for hyperinflammation and MAS. Collectively, the data generated herein will increase our understanding on how the inflammatory environment together with specific anti-inflammatory medication may pre-dispose for MAS and whether monitoring of type 1 interferon signatures in sJIA patients can support prediction of hyperinflammation. Our data may further help to identify a caveat of the otherwise highly successful IL-1 therapy, which in specific scenarios (genetic pre-disposition, nature of the infectious trigger) may in fact pose a risk factor.