Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Department of Neurology, H. Houston Merritt Center and Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, USA.
J Mol Med (Berl). 2022 Jun;100(6):963-971. doi: 10.1007/s00109-022-02206-2. Epub 2022 May 30.
Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.3243A > G mutation or single, large-scale mtDNA deletions, we examined (i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure and (ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose-response experiments to determine the half-maximal effective LPS concentration (EC), relative to controls, leukocytes from patients with mtDNA deletions showed 74-79% lower responses for IL-6 and IL-1β (p = 0.031, p = 0.009). Moreover, whole blood from patients with mtDNA deletions (p = 0.006), but not patients with the m.3243A > G mutation, showed greater sensitivity to the immunosuppressive effects of dexamethasone. Together, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and increase the sensitivity to immune cytokine suppression by glucocorticoids. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes. KEY MESSAGES: Little is known about leukocyte cytokine responses in patients with mitochondrial diseases. Leukocytes of patients with mtDNA deletions show blunted LPS sensitivity and cytokine responses. Leukocytes of patients with mtDNA deletions are more sensitive to glucocorticoid-mediated IL-6 suppression. Work in larger cohorts is needed to delineate potential immune alterations in mitochondrial diseases.
患有氧化磷酸化（OxPhos）缺陷导致线粒体疾病的患者似乎特别容易受到感染。尽管 OxPhos 缺陷在体外和动物模型中调节细胞因子的产生，但对于遗传性线粒体 DNA（mtDNA）缺陷患者的循环白细胞如何对急性免疫挑战做出反应，知之甚少。在一个由 21 名健康对照者（对照组）和 12 名患有 m.3243A>G 突变或单个大片段 mtDNA 缺失的患者组成的小队列中，我们检测了（i）急性脂多糖（LPS）暴露后细胞因子（IL-6、TNF-α、IL-1β）的反应，以及（ii）细胞因子产生对糖皮质激素信号（地塞米松）免疫抑制作用的敏感性。在确定半最大有效 LPS 浓度（EC）的剂量反应实验中，与对照组相比，mtDNA 缺失患者的白细胞对 IL-6 和 IL-1β 的反应降低了 74-79%（p=0.031，p=0.009）。此外，mtDNA 缺失患者的全血（p=0.006）而非 m.3243A>G 突变患者的全血对地塞米松的免疫抑制作用更敏感。这些体外数据初步表明，一些系统性 OxPhos 缺陷可能会损害免疫细胞因子反应，并增加糖皮质激素对免疫细胞因子抑制的敏感性。需要在更大的队列中开展进一步的工作，以明确线粒体疾病患者免疫失调的性质及其对疾病表型的潜在影响。
对于线粒体疾病患者的白细胞细胞因子反应知之甚少。
mtDNA 缺失患者的白细胞对 LPS 的敏感性和细胞因子反应减弱。
mtDNA 缺失患者的白细胞对地塞米松介导的 IL-6 抑制更为敏感。
需要在更大的队列中开展工作，以阐明线粒体疾病中的潜在免疫改变。
