干扰素-β纠正多发性硬化症中的大量基因失调：对免疫调节和神经保护的短期和长期影响。
Interferon-β corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection.
机构信息
Department of Neurology and the Grossman Institute for Neuroscience, Quantitative Biology and Human Behavior, University of Chicago, Chicago, IL 60637, United States.
Center for Research Informatics, University of Chicago, Chicago, IL 60637, United States; Department of Paediatrics, University of Chicago, Chicago, IL 60637, United States; Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, United States.
出版信息
EBioMedicine. 2019 Nov;49:269-283. doi: 10.1016/j.ebiom.2019.09.059. Epub 2019 Oct 21.
BACKGROUND
In multiple sclerosis (MS), immune up-regulation is coupled to subnormal immune response to interferon-β (IFN-β) and low serum IFN-β levels. The relationship between the defect in IFN signalling and acute and long-term effects of IFN-β on gene expression in MS is inadequately understood.
METHODS
We profiled IFN-β-induced transcriptome shifts, using high-resolution microarrays on 227 mononuclear cell samples from IFN-β-treated MS Complete Responders (CR) stable for five years, and stable and active Partial Responders (PR), stable and active untreated MS, and healthy controls.
FINDINGS
IFN-β injection induced short-term changes in 1,200 genes compared to baseline expression after 4-day IFN washout. Pre-injection after washout, and in response to IFN-β injections, PR more frequently had abnormal gene expression than CR. Surprisingly, short-term IFN-β induced little shift in Th1/Th17/Th2 gene expression, but up-regulated immune-inhibitory genes (ILT, IDO1, PD-L1). Expression of 8,800 genes was dysregulated in therapy-naïve compared to IFN-β-treated patients. These long-term changes in protein-coding and long non-coding RNAs affect immunity, synaptic transmission, and CNS cell survival, and correct the disordered therapy-naïve transcriptome to near-normal. In keeping with its impact on clinical course and brain repair in MS, long-term IFN-β treatment reversed the overexpression of proinflammatory and MMP genes, while enhancing genes involved in the oligodendroglia-protective integrated stress response, neuroprotection, and immunoregulation. In the rectified long-term signature, 277 transcripts differed between stable PR and CR patients.
INTERPRETATION
IFN-β had minimal short-term effects on Th1 and Th2 pathways, but long-term it corrected gene dysregulation and induced immunoregulatory and neuroprotective genes. These data offer new biomarkers for IFN-β responsiveness.
FUNDING
Unrestricted grants from the US National MS Society, NMSS RG#4509A, and Bayer Pharmaceuticals.
背景
在多发性硬化症（MS）中，免疫上调与对干扰素-β（IFN-β）的免疫反应不足以及血清 IFN-β 水平低有关。IFN 信号转导缺陷与 IFN-β 对 MS 基因表达的急性和长期影响之间的关系尚未充分了解。
方法
我们使用高分辨率微阵列对 227 个来自 IFN-β 治疗的 MS 完全缓解者（CR）、稳定的 5 年的单核细胞样本进行了 IFN-β 诱导的转录组谱分析，以及稳定和活跃的部分缓解者（PR）、稳定和活跃的未经治疗的 MS 患者和健康对照组。
结果
与 IFN 洗脱后 4 天的基线表达相比，IFN-β 注射诱导了 1200 个基因的短期变化。在洗脱后的预注射和对 IFN-β 注射的反应中，PR 比 CR 更频繁地出现异常基因表达。令人惊讶的是，短期 IFN-β 诱导 Th1/Th17/Th2 基因表达的变化很小，但上调了免疫抑制基因（ILT、IDO1、PD-L1）。与接受 IFN-β 治疗的患者相比，未经治疗的患者有 8800 个基因的表达失调。这些蛋白质编码和长非编码 RNA 的长期变化影响免疫、突触传递和中枢神经系统细胞存活，并使紊乱的未经治疗的转录组接近正常。与 IFN-β 治疗对 MS 临床病程和大脑修复的影响一致，长期 IFN-β 治疗逆转了促炎和 MMP 基因的过度表达，同时增强了与少突胶质细胞保护综合应激反应、神经保护和免疫调节相关的基因。在纠正的长期特征中，稳定的 PR 和 CR 患者之间有 277 个转录本不同。
解释
IFN-β 对 Th1 和 Th2 途径的短期影响很小，但长期来看，它纠正了基因失调，并诱导了免疫调节和神经保护基因。这些数据为 IFN-β 反应性提供了新的生物标志物。
资金
美国国家多发性硬化症协会（NMSS RG#4509A）和拜耳制药公司的无限制赠款。
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