Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease.

IF 8.1 1区医学 Q1 CLINICAL NEUROLOGY

Annals of Neurology Pub Date : 2024-09-25 DOI:10.1002/ana.27081

Nandaki Keshavan, Lana Mhaldien, Kimberly Gilmour, Shamima Rahman

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Abstract

Objective: Mitochondria are implicated in regulation of the innate immune response. We hypothesized that abnormalities in interferon signaling may contribute to pathophysiology in patients with primary mitochondrial disease (PMD).

Methods: Expression of interferon stimulated genes (ISGs) was measured by real-time polymerase chain reaction (PCR) in whole blood samples from a cohort of patients with PMD.

Results: Upregulated ISG expression was observed in a high proportion (41/55, 75%) of patients with PMD on at least 1 occasion, most frequently IFI27 upregulation, seen in 50% of the samples. Some patients had extremely high IFI27 levels, similar to those seen in patients with primary interferonopathies. A statistically significant correlation was observed between elevated IFI27 gene expression and PMD, but not between IFI27 and secondary mitochondrial dysfunction, suggesting that ISG upregulation is a biomarker of PMD. In some patients with PMD, ISG abnormalities persisted on repeat measurement over several years, indicative of ongoing chronic inflammation. Subgroup analyses suggested common ISG signatures in patients with similar mitochondrial disease mechanisms and positive correlations with disease severity among patients with identical genetic diagnoses.

Interpretation: Dysregulated interferon signaling is frequently seen in patients with PMD suggesting that interferon dysregulation is a contributor to pathophysiology. This may indicate a role for repurposing of immunomodulatory therapies for the treatment of PMDs by targeting interferon signaling. ANN NEUROL 2024.

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干扰素刺激基因表达是原发性线粒体疾病的生物标志物

目的线粒体与先天性免疫反应的调节有关。我们假设干扰素信号传导异常可能会导致原发性线粒体疾病（PMD）患者的病理生理学：方法：在一组原发性线粒体病（PMD）患者的全血样本中，通过实时聚合酶链反应（PCR）测量干扰素刺激基因（ISGs）的表达：结果：在很高比例的 PMD 患者（41/55，75%）中至少有一次观察到 ISG 表达上调，最常见的是 IFI27 上调，见于 50%的样本中。一些患者的IFI27水平极高，与原发性干扰素病患者的情况类似。据统计，IFI27 基因表达升高与 PMD 之间存在明显的相关性，但 IFI27 与继发性线粒体功能障碍之间不存在相关性，这表明 ISG 上调是 PMD 的生物标志物。在一些 PMD 患者中，ISG 异常在重复测量时持续数年，表明慢性炎症仍在持续。分组分析表明，在具有相似线粒体疾病机制的患者中存在共同的ISG特征，在具有相同基因诊断的患者中，ISG特征与疾病严重程度呈正相关：在 PMD 患者中经常出现干扰素信号失调，这表明干扰素失调是病理生理学的一个因素。这可能表明，以干扰素信号为靶点的免疫调节疗法在治疗原发性骨髓增生异常综合征方面具有重新定位的作用。ann neurol 2024.

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Annals of Neurology 医学-临床神经学

CiteScore

18.00

自引率

1.80%

发文量

270

审稿时长

3-8 weeks

期刊介绍： Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.