Département de microbiologie et immunologie, Faculté de Médecine de l'Université Laval, Centre de Recherche du CHU de Québec-Université Laval, Québec City, QC, Canada.
Département de mathématiques et statistiques, Université Laval, Québec City, QC, Canada.
Front Immunol. 2019 May 10;10:1026. doi: 10.3389/fimmu.2019.01026. eCollection 2019.
The mitochondrion supplies energy to the cell and regulates apoptosis. Unlike other mammalian organelles, mitochondria are formed by binary fission and cannot be directly produced by the cell. They contain numerous copies of a compact circular genome that encodes RNA molecules and proteins involved in mitochondrial oxidative phosphorylation. Whereas, mitochondrial DNA (mtDNA) activates the innate immune system if present in the cytosol or the extracellular milieu, it is also the target of circulating autoantibodies in systemic lupus erythematosus (SLE). However, it is not known whether mitochondrial RNA is also recognized by autoantibodies in SLE. In the present study, we evaluated the presence of autoantibodies targeting mitochondrial RNA (AmtRNA) in SLE. We quantified AmtRNA in an inducible model of murine SLE. The AmtRNA were also determined in SLE patients and healthy volunteers. AmtRNA titers were measured in both our induced model of murine SLE and in human SLE, and biostatistical analyses were performed to determine whether the presence and/or levels of AmtRNA were associated with clinical features expressed by SLE patients. Both IgG and IgM classes of AmtRNA were increased in SLE patients ( = 86) compared to healthy controls ( = 30) ( < 0.0001 and = 0.0493, respectively). AmtRNA IgG levels correlated with anti-mtDNA-IgG titers ( = 0.54, < 0.0001) as well as with both IgG and IgM against β-2-glycoprotein I (anti-βGPI; = 0.22, = 0.05), and AmtRNA-IgG antibodies were present at higher levels when patients were positive for autoantibodies to double-stranded-genomic DNA ( < 0.0001). AmtRNA-IgG were able to specifically discriminate SLE patients from healthy controls, and were negatively associated with plaque formation ( = 0.04) and lupus nephritis ( = 0.03). Conversely, AmtRNA-IgM titers correlated with those of anti-βGPI-IgM ( = 0.48, < 0.0001). AmtRNA-IgM were higher when patients were positive for anticardiolipin antibodies (aCL-IgG: = 0.01; aCL-IgM: = 0.002), but AmtRNA-IgM were not associated with any of the clinical manifestations assessed. These findings identify mtRNA as a novel mitochondrial antigen target in SLE, and support the concept that mitochondria may provide an important source of circulating autoantigens in SLE.
线粒体为细胞提供能量并调节细胞凋亡。与其他哺乳动物细胞器不同，线粒体通过二分分裂形成，不能由细胞直接产生。它们含有大量的紧凑圆形基因组，该基因组编码参与线粒体氧化磷酸化的 RNA 分子和蛋白质。然而，如果线粒体 DNA（mtDNA）存在于细胞质或细胞外环境中，它会激活先天免疫系统，同时也是系统性红斑狼疮（SLE）中循环自身抗体的靶标。但是，尚不清楚 SLE 中的自身抗体是否也能识别线粒体 RNA。在本研究中，我们评估了 SLE 中针对线粒体 RNA（AmtRNA）的自身抗体的存在情况。我们在诱导的 SLE 小鼠模型中定量了 AmtRNA。还在 SLE 患者和健康志愿者中确定了 AmtRNA。在我们诱导的 SLE 小鼠模型和人类 SLE 中测量了 AmtRNA 滴度，并进行了生物统计学分析，以确定 AmtRNA 的存在和/或水平是否与 SLE 患者的临床特征相关。与健康对照组（=30）相比，SLE 患者的 IgG 和 IgM 类 AmtRNA 均升高（=86）（<0.0001 和=0.0493，分别）。AmtRNA IgG 水平与抗 mtDNA-IgG 滴度相关（=0.54，<0.0001），以及与针对β-2-糖蛋白 I（抗-βGPI；=0.22，=0.05）的 IgG 和 IgM 相关，并且当患者自身抗体针对双链基因组 DNA 呈阳性时，AmtRNA-IgG 抗体的水平更高（<0.0001）。AmtRNA-IgG 能够特异性地区分 SLE 患者与健康对照者，并且与斑块形成呈负相关（=0.04）和狼疮肾炎呈负相关（=0.03）。相反，AmtRNA-IgM 滴度与抗-βGPI-IgM 相关（=0.48，<0.0001）。当患者抗心磷脂抗体（aCL-IgG：=0.01；aCL-IgM：=0.002）阳性时，AmtRNA-IgM 较高，但 AmtRNA-IgM 与评估的任何临床表现均无关。这些发现确定了 mtRNA 为 SLE 中的新型线粒体抗原靶标，并支持了线粒体可能为 SLE 中循环自身抗原的重要来源的概念。
