{"title":"干扰素刺激基因表达是原发性线粒体疾病的生物标志物","authors":"Nandaki Keshavan MRCPCH, PhD, Lana Mhaldien MSc, Kimberly Gilmour PhD, Shamima Rahman FRCP, PhD","doi":"10.1002/ana.27081","DOIUrl":null,"url":null,"abstract":"<div>\n \n <section>\n \n <h3> Objective</h3>\n \n <p>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).</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>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.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Upregulated ISG expression was observed in a high proportion (41/55, 75%) of patients with PMD on at least 1 occasion, most frequently <i>IFI27</i> upregulation, seen in 50% of the samples. Some patients had extremely high <i>IFI27</i> levels, similar to those seen in patients with primary interferonopathies. A statistically significant correlation was observed between elevated <i>IFI27</i> gene expression and PMD, but not between <i>IFI27</i> 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.</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>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;96:1185–1200</p>\n </section>\n </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"96 6","pages":"1185-1200"},"PeriodicalIF":8.1000,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27081","citationCount":"0","resultStr":"{\"title\":\"Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease\",\"authors\":\"Nandaki Keshavan MRCPCH, PhD, Lana Mhaldien MSc, Kimberly Gilmour PhD, Shamima Rahman FRCP, PhD\",\"doi\":\"10.1002/ana.27081\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>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).</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Upregulated ISG expression was observed in a high proportion (41/55, 75%) of patients with PMD on at least 1 occasion, most frequently <i>IFI27</i> upregulation, seen in 50% of the samples. Some patients had extremely high <i>IFI27</i> levels, similar to those seen in patients with primary interferonopathies. A statistically significant correlation was observed between elevated <i>IFI27</i> gene expression and PMD, but not between <i>IFI27</i> 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.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Interpretation</h3>\\n \\n <p>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;96:1185–1200</p>\\n </section>\\n </div>\",\"PeriodicalId\":127,\"journal\":{\"name\":\"Annals of Neurology\",\"volume\":\"96 6\",\"pages\":\"1185-1200\"},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2024-09-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27081\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/ana.27081\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/ana.27081","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
Interferon Stimulated Gene Expression Is a Biomarker for Primary Mitochondrial Disease
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;96:1185–1200
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.
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