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)

吞噬细胞衍生的 S100A12 复合物和 IL-17/IFNγ 的 T 细胞表达作为系统性幼年特发性关节炎 (sJIA) 中先天性和适应性免疫失调的因素

• 批准号: 407661645
• 负责人: Professor Dr. Dirk Föll
• 金额: --
• 依托单位: Klinik für Rheumatologie und klinischen Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/407661645?language=en
• 关键词: Phagocyte; derived; S100A12; complexes; cell

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.

全身性幼年特发性关节炎（sJIA）是儿童时期最严重的风湿性关节病。在其全身阶段，它是一种具有显著发病率的自身炎症性疾病。我们以前已经表明，吞噬细胞衍生的钙结合S100蛋白有助于在这个起始阶段的自身炎症。S100 A12是一种促炎性“警报素”，通过Toll样受体4（TLR 4）信号传导激活单核细胞，并在活性sJIA血清中以高浓度出现。重要的是，我们刚刚证明血清S100 A12，特别是IL-1b和IL-18，可以促进sJIA中IL-17的过度表达。IL-17过表达的CD 4 T细胞似乎特别敏感的治疗IL-1b的封锁。相反，sJlA CD 4 + T细胞没有显示IL-17表达增加，但产生了令人惊讶的有限IFN γ应答。我们的患者数据与最近提出的sJIA小鼠模型惊人一致，该模型在IFN γ-/-背景下呈现出其最显著的临床表型，并且在疾病病理学中依赖于表达IL-17的CD 3 T细胞。IFN γ被认为是sJIA中的潜在主开关：小鼠模型以及我们的患者数据表明低水平有助于自身免疫性关节炎的进展，而IFN γ过表达可能驱动巨噬细胞活化综合征（MAS），作为最严重的系统性sJIA并发症之一。我们目前的建议旨在了解sJIA中T细胞细胞因子表达的偏斜，重点是失衡的IFN γ。将研究CD 4 + T细胞的谱系分化和细胞因子表达细胞的扩增，特别是在血清因子如S100 A12、IL-1、IL-18和IL-6（如在sJIA中过表达）或IL-7和IL-15（如由S100 A12差异调节）存在下。此外，我们将研究CD 8 + T细胞对sJIA中细胞因子特征的贡献以及它们在调节CD 4 + T细胞的细胞因子表达中的作用。然而，来自我们的sJIA患者研究的未发表数据表明IFN γ特别是CD 8 + T细胞的大量上调，并且这些细胞负调节CD 4 + T细胞细胞因子表达。最后，我们的目的是研究S100 A12对sJIA小鼠模型中疾病发展的贡献，利用野生型以及IFNy低或IFNy-/-背景的S100 A12 tg动物。我们的总体目标是了解sJIA中以内源性TLR 4配体S100 A12的强烈过表达为特征的无菌炎症环境是否可以导致独特的细胞因子环境将IL-17和IFN γ产生极化为不同的细胞群体，这对于sJIA发病机制至关重要。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。