Decades-long elevation of interferon-alpha can initiate and drive Sjogren syndrome I

Sjogren syndrome (SS) is a chronic inflammatory disease with no effective targeted treatments. There is a pressing need to identify targetable pathways which drive disease. Here we combine ultrasensitive detection of IFN-a with proteomic approaches in two cohorts including UK Biobank to demonstrate that IFN-a is elevated in the majority of individuals with SS, and this elevation can precede diagnosis by 15 years and persists for 30 years. We identify a distinct immunological phenotype associated with elevated IFN-a characterised by peripheral blood cytopenias, hypergammaglobulinaemia and SS-specific autoantibody formation. To address a causal role for chronic interferon elevation in initiating and driving these immunological features we created a novel model of systemic chronic IFN-a elevation upon overexpression of Ifna4 in conventional dendritic cells type 1 of mice. This model recapitulates the key IFN-a -associated features we identified in clinical studies and can be effectively treated by IFNAR1-blocking monoclonal antibodies. In summary chronically elevated IFN-a can initiate and drive immunopathological features of SS and represents a therapeutic target. Overall design: Transcriptomic investigation of whole spleen in anti_IFNAR1 and isotype treated Clec9a-Cre IFNa4KI mice.

干燥综合征（Sjogren syndrome, SS）是一类尚无有效靶向治疗方案的慢性炎症性疾病，当前亟需挖掘驱动疾病进展的可靶向致病通路。本研究在包括英国生物银行（UK Biobank）在内的两个队列中，将干扰素-α（IFN-α）的超灵敏检测技术与蛋白质组学方法相结合，证实多数干燥综合征患者体内IFN-α水平显著升高，且该升高现象可早于临床诊断15年出现，并可持续长达30年之久。研究团队鉴定出一种与IFN-α升高相关的独特免疫学表型，其特征为外周血细胞减少症、高丙种球蛋白血症以及干燥综合征特异性自身抗体生成。为明确慢性干扰素升高在启动并驱动上述免疫学特征中的因果作用，本研究通过在小鼠1型常规树突状细胞中过表达Ifna4基因，构建了一种全新的系统性慢性IFN-α升高模型。该模型可重现我们在临床研究中鉴定出的IFN-α相关核心病理特征，且可通过靶向阻断IFNAR1的单克隆抗体实现有效治疗。综上，慢性IFN-α升高可启动并驱动干燥综合征的免疫病理进程，可作为潜在治疗靶点。
实验设计方案：对抗IFNAR1治疗组与同型对照治疗组的Clec9a-Cre IFNa4KI小鼠的全脾脏组织开展转录组学分析。