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.

全身少年特发性关节炎（SJIA）是儿童时期风湿性疾病最严重的形式。在其系统阶段，它是一种具有明显发病率的自发性疾病。我们先前已经表明，在此开始阶段，吞噬细胞衍生的钙结合S100蛋白有助于自身炎症。 S100A12自发性患者中性粒细胞自发释放是一种促炎的“警报蛋白”，可通过Toll样受体4（TLR4）信号传导激活单核细胞，并在活性SJIA血清中以高浓度出现。重要的是，我们刚刚证明，血清S100A12与尤其是IL-1B和IL-18的一致性可以促进SJIA中YDT细胞IL-17的过表达。 YDT细胞的IL-17过表达似乎对治疗性IL-1B阻滞特别敏感。相反，SJIA CD4+ T细胞没有揭示IL-17表达增加，但IFNY响应的效果非常有限。我们的患者数据在最近提出的SJIA小鼠模型中处于引人注目的线上，该模型在IFNY - / - 背景上呈现了最明显的临床表型，并且取决于IL-17在疾病病理学中表达YDT细胞的IL-17。 IFNY被认为是SJIA的潜在主开关：鼠模型以及我们的患者数据表明，较低的水平有助于自身免疫性关节炎的进展，而IFNY-ERVERSESS可能会导致巨噬细胞激活综合征（MAS）作为最严重的SJIA 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，重点是功能障碍IFNY。将研究CD4+ T细胞，以使细胞因子表达细胞的谱系分化和扩展，特别是在SJIA中的S100A12，IL-1，IL-18和IL-6等血清因子的存在下，或IL-7和IL-15中过表达，因为由S100A12差异调节。此外，我们将研究CD8+ T细胞对SJIA中细胞因子特征的贡献，以及它们在通过CD4+ T细胞调节细胞因子表达中的作用。然而，我们的SJIA患者研究中未发表的数据表明，特别是CD8+ T细胞和这些细胞对IFNY的大规模上调，以负调节CD4+ T细胞细胞因子的表达。最后，我们的目标是使用S100A12对SJIA小鼠模型的疾病发展的贡献，利用S100A12TG动物在Wildtype以及Ifnylow或Ifnylow或Ifny - / - 背景上的贡献。我们的总体目标是了解SJIA的无菌炎症环境的特征是内源性TLR4配体S100A12的强烈过表达是否会导致独特的细胞因子环境极化IL-17以及IFNY生产到不同细胞群体，这对于SJIA病原体至关重要。了解先天性和适应性免疫之间的串扰可能有助于更好地理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。