Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale UMR 1163, Paris, France.
University of Paris, Imagine Institute, Paris, France.
J Exp Med. 2021 Sep 6;218(9). doi: 10.1084/jem.20210501. Epub 2021 Jul 15.
Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype.
常染色体隐性蛋白激酶 C δ（PKCδ）缺陷的患者患有儿童期发病的自身免疫性疾病，包括系统性红斑狼疮。他们还经常发生感染，这与吞噬细胞 NADPH 氧化酶缺陷导致的慢性肉芽肿病（CGD）患者的感染重叠，CGD 是一种由于活性氧（ROS）产生不足引起的疾病。我们研究了一个由 17 名 PKCδ 缺陷患者组成的国际队列，发现他们的 EBV-B 细胞和单核细胞衍生的吞噬细胞仅产生少量 ROS，并且在用 PMA 或调理的金黄色葡萄球菌刺激后不能正常磷酸化 p40phox。此外，患者的循环吞噬细胞显示出 ROS 产生的异常低水平和明显减少的中性粒细胞胞外陷阱形成，这表明 PKCδ 在 NADPH 氧化酶复合物的激活中起作用。我们的研究结果表明，PKCδ 缺陷患者在各种髓样细胞亚群中 NADPH 氧化酶活性受损，这可能导致其 CGD 样感染表型。
