Phagocyte-derived S100A12 complexes and T cell expression of IL-17/IFNγ as factors linking innate and adaptive immune dysregulation in systemic Juvenile Idiopathic Arthritis (sJIA)

系统性幼年特发性关节炎（sJIA）是儿童时期最严重的风湿性关节疾病。在全身性阶段，它是一种发病率很高的自身炎症性疾病。我们之前已经证明，吞噬细胞来源的钙结合S100蛋白在这一起始阶段有助于自身炎症。S100A12从自身炎症患者中性粒细胞中自发释放，是一种促炎“警报素”，通过toll样受体4 （TLR4）信号传导激活单核细胞，并在活性sJIA血清中高浓度出现。重要的是，我们刚刚证明了血清S100A12，特别是IL-1b和IL-18，可以促进sJIA中ydT细胞IL-17的过表达。ydT细胞IL-17过表达似乎对治疗性IL-1b阻断特别敏感。相反，sJIA CD4+ T细胞没有显示IL-17表达增加，但出现了令人惊讶的有限的IFNy应答。我们的患者数据与最近提出的sJIA小鼠模型一致，该模型在IFNy-/-背景下表现出最明显的临床表型，并且在疾病病理中依赖于IL-17表达的ydT细胞。IFNy被认为是sJIA的潜在主开关：小鼠模型和我们的患者数据表明，低水平的IFNy有助于自身免疫性关节炎的进展，而IFNy过表达可能驱动巨噬细胞激活综合征（MAS）作为最严重的系统性sJIA并发症之一。我们目前的研究旨在了解sJIA中T细胞细胞因子表达的偏斜，重点是IFNy的不平衡。将研究CD4+ T细胞的谱系分化和细胞因子表达细胞的扩增，特别是存在sJIA中过度表达的血清因子，如S100A12、IL-1、IL-18和IL-6，或S100A12差异调节的IL-7和IL-15。进一步，我们将研究CD8+ T细胞对sJIA细胞因子特征的贡献及其在CD4+ T细胞调节细胞因子表达中的作用。然而，我们在sjia患者研究中未发表的数据表明，特别是CD8+ T细胞大量上调IFNy，这些细胞负性调节CD4+ T细胞细胞因子的表达。最后，我们的目标是研究S100A12在sJIA小鼠模型中对疾病发展的贡献，利用野生型S100A12tg动物以及IFNylow或IFNy-/-背景。我们的总体目标是了解sJIA的无菌炎症环境（以内源性TLR4配体S100A12的强烈过表达为特征）是否会导致独特的细胞因子环境，使IL-17和IFNy的产生分化到不同的细胞群，这对sJIA的发病至关重要。了解先天免疫和适应性免疫之间的相互作用可能有助于更好地了解这种使人衰弱的疾病的自然过程，并促进产生更有针对性的方法来监测和治疗sJIA。

Systemic Juvenile Idiopathic Arthritis (sJIA) is the most severe form of rheumatic joint disease in childhood. In its systemic phase, it is an autoinflammatory disease with significant morbidity. We have previously shown that phagocyte-derived calcium-binding S100 proteins contribute to autoinflammation in this initiation phase. S100A12 spontaneously released from autoinflammatory patient neutrophils is a pro-inflammatory "alarmin" that activates monocytes via Toll-like receptor 4 (TLR4) signalling and appears at high concentrations in active sJIA serum. Importantly, we just demonstrated that serum S100A12, in concert with particularly IL-1b and IL-18, can promote overexpression of ydT cellular IL-17 in sJIA. IL-17 overexpression by ydT cells appears particularly sensitive to therapeutic IL-1b blockade. On the contrary, sJIA CD4+ T cells did not reveal increased IL-17 expression but mounted a surprisingly limited IFNy response. Our patient data are in striking line with a recently proposed sJIA mouse model, which presented its most pronounced clinical phenotype on IFNy-/- background and depends on IL-17 expressing ydT cells in disease pathology. IFNy is considered as potential master-switch in sJIA: Murine model as well as our patient data indicate low levels to contribute to the progression of autoimmune arthritis, while IFNy-overexpression may drive macrophage activation syndrome (MAS) as one of the most severe systemic sJIA complications. Our present proposal aims to understand the skewing of T cellular cytokine expression in sJIA, with emphasis on dysbalanced IFNy. CD4+ T cells will be studied for lineage differentiation and expansion of cytokine expressing cells, particularly in presence of serum factors such as S100A12, IL-1, IL-18 and IL-6 as over-expressed in sJIA, or IL-7 and IL-15 as differentially regulated by S100A12. Further, we will investigate the contribution of CD8+ T cells to cytokine signatures in sJIA and their role in modulating cytokine expression by CD4+ T cells. Yet unpublished data from our sJIA-patient studies suggest a massive upregulation of IFNy by particularly CD8+ T cells and these cells to negatively regulate CD4+ T cellular cytokine expression. Finally we aim to sudy the contribution of S100A12 to disease development in the sJIA mouse model, utilizing S100A12tg animals on wildtype as well as IFNylow or IFNy-/- background. Our overall goal is to understand whether the sterile inflammatory environment in sJIA, characterized by a strong overexpression of the endogenous TLR4 ligand S100A12, can result in a unique cytokine environment polarizing IL-17 and IFNy production to distinct cell populations, which are crucial for sJIA pathogenesis. Understanding the cross-talk between innate and adaptive immunity may help to better understand the natural course of this debilitating disease and foster the generation of more targeted approaches to monitor and treat sJIA.