Spondyloarthritis (SpA) represents a family of inflammatory diseases of the spine and peripheral joints. Ankylosing spondylitis (AS) is the prototypic form of SpA in which progressive disease can lead to fusion of the spine. Therapeutically, knowledge of type 3 immunity has translated into the development of IL-23– and IL-17A–blocking antibodies for the treatment of SpA. Despite being able to provide symptomatic control, the current biologics do not prevent the fusion of joints in AS patients. Thus, there is an unmet need for disease-modifying drugs. Genetic studies have linked the Janus kinase TYK2 to AS. TYK2 is a mediator of type 3 immunity through intracellular signaling of IL-23. Here, we describe and characterize a potentially novel small-molecule inhibitor of TYK2 that blocked IL-23 signaling in vitro and inhibited disease progression in animal models of SpA. The effect of the inhibitor appears to be TYK2 specific, using TYK2-inactive mice, which further revealed a duality in the induction of IL-17A and IL-22 by IL-23. Specifically, IL-22 production was TYK2/JAK2/STAT3 dependent, while IL-17A was mostly JAK2 dependent. Finally, we examined the effects of AS-associated TYK2 SNPs on TYK2 expression and function and correlated them with AS disease progression. This work provides evidence that TYK2 inhibitors have great potential as an orally delivered therapeutic for SpA.

中文翻译：

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TYK2抑制作用会降低3型免疫力，并改变鼠脊椎关节炎的疾病进展。

脊柱关节炎（SpA）代表脊柱和周围关节的炎性疾病。强直性脊柱炎（AS）是SpA的原型形式，其中进行性疾病可导致脊柱融合。在治疗上，对3型免疫的了解已转化为可治疗SpA的IL-23和IL-17A阻断抗体的开发。尽管能够提供对症控制，但是目前的生物制剂并不能阻止AS患者的关节融合。因此，对疾病改善药物的需求尚未得到满足。遗传研究已将Janus激酶TYK2与AS连锁。TYK2是通过IL-23的细胞内信号传导介导的3型免疫的介质。这里，我们描述并描述了潜在的新型TYK2小分子抑制剂，该抑制剂可在体外阻断IL-23信号传导并在SpA动物模型中抑制疾病进展。使用无TYK2的小鼠，抑制剂的作用似乎是TYK2特异性的，这进一步揭示了IL-23诱导IL-17A和IL-22的双重性。具体而言，IL-22的产生依赖于TYK2 / JAK2 / STAT3，而IL-17A则主要依赖于JAK2。最后，我们检查了与AS相关的影响TYK2 SNPs对TYK2表达和功能的影响及其与AS疾病进展的相关性。这项工作提供了证据，表明TYK2抑制剂作为SpA的口服治疗剂具有巨大潜力。