背景:自身免疫性疾病是健康不良和发病的主要原因,并且具有多种病因。两条信号通路是自身免疫病理学的关键驱动因素,干扰素和NFκB/RelA,定义干扰素病和光病的两个广泛标记。先前的工作确定NFκB亚基RelB的功能的遗传丧失导致小鼠和人类的自身免疫和炎性病理学。
目的:我们试图通过无偏分析免疫前哨细胞的刺激反应来表征RelB缺陷型自身免疫,并确定失调基因程序在RelB缺陷病理中的功能作用。
方法:对来自RelB缺陷患者和基因敲除小鼠的成纤维细胞和树突状细胞进行转录组学分析,在缺乏RelB和I型干扰素受体的小鼠中评估转录组反应和病理学。
结果:我们发现患者来源的成纤维细胞和小鼠骨髓细胞中RelB的缺失导致数百个干扰素刺激基因的诱导升高。去除干扰素刺激的基因程序的高表达并不能改善RelB敲除小鼠的自身免疫病理学。相反,我们发现RelB抑制一组不同的炎症反应基因,其方式独立于干扰素信号传导,但与NFκB结合基序相关.
结论:虽然转录组学分析将RelB缺陷的自身免疫性疾病描述为干扰素病,遗传证据表明,小鼠的病理是干扰素无关的。
Autoimmune diseases are leading causes of ill health and morbidity and have diverse etiology. Two signaling pathways are key drivers of autoimmune pathology, interferon and nuclear factor-κB (NF-κB)/RelA, defining the 2 broad labels of interferonopathies and relopathies. Prior work has established that genetic loss of function of the NF-κB subunit RelB leads to autoimmune and inflammatory pathology in mice and humans.
We sought to characterize RelB-deficient autoimmunity by unbiased profiling of the responses of immune sentinel cells to stimulus and to determine the functional role of dysregulated gene programs in the RelB-deficient pathology.
Transcriptomic profiling was performed on fibroblasts and dendritic cells derived from patients with RelB deficiency and knockout mice, and transcriptomic responses and pathology were assessed in mice deficient in both RelB and the type I interferon receptor.
We found that loss of RelB in patient-derived fibroblasts and mouse myeloid cells results in elevated induction of hundreds of interferon-stimulated genes. Removing hyperexpression of the interferon-stimulated gene program did not ameliorate the autoimmune pathology of RelB knockout mice. Instead, we found that RelB suppresses a different set of inflammatory response genes in a manner that is independent of interferon signaling but associated with NF-κB binding motifs.
Although transcriptomic profiling would describe RelB-deficient autoimmune disease as an
interferonopathy, the genetic evidence indicates that the pathology in mice is interferon-independent.