Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17609-14. doi: 10.1073/pnas.1209724109. Epub 2012 Oct 8.
Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ-induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy.
阐明在病理性组织中活跃的分子途径对于定义疾病亚群、选择治疗方法和监测疾病活动具有重要意义。针对 IFN-α或 IFN-γ的治疗方法的发展使得发现能够准确报告不同 IFN 途径活性的探针成为当务之急。我们表明，尽管 I 型和 II 型 IFN 诱导表达大量重叠的分子群，但可以定义 IFN-γ活性的精确探针。这些探针联合使用时，在干燥综合征 (SS) 组织中显示出明显的 IFN-γ效应。相比之下，皮肌炎肌肉表现出主要的 I 型 IFN 模式。有趣的是，SS 患者的 IFN 特征存在异质性，一些患者表现出主要的 I 型模式。生化模式在很大程度上将 SS 患者的靶组织与皮肌炎患者区分开来，并为特定活检中不同 IFN 途径的影响提供了相对权重。在 SS 中，I 型和 II 型 IFN 效应定位于相同的上皮细胞，周围是表达 IFN-γ诱导蛋白的炎症细胞，表明存在增强的相互作用。在复杂风湿性疾病的组织中，针对不同 IFN 途径的精确探针对于疾病分类、发病机制阐明和治疗选择至关重要。
