Waschbisch Anne, Schröder Sina, Schraudner Dana, Sammet Laura, Weksler Babette, Melms Arthur, Pfeifenbring Sabine, Stadelmann Christine, Schwab Stefan, Linker Ralf A
Department of Neurology, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, NY 10065; and.
J Immunol. 2016 Feb 15;196(4):1558-67. doi: 10.4049/jimmunol.1501960. Epub 2016 Jan 8.
Monocytes represent a heterogeneous population of primary immune effector cells. At least three different subsets can be distinguished based on expression of the low-affinity FcγRIII: CD14(++)CD16 -: classical monocytes, CD14(++)CD16(+) intermediate monocytes, and CD14(+)CD16 ++: non-classical monocytes. Whereas CD16 -: classical monocytes are considered key players in multiple sclerosis (MS), little is known on CD16(+) monocytes and how they contribute to the disease. In this study, we examined the frequency and phenotype of monocyte subpopulations in peripheral blood, cerebrospinal fluid (CSF), and brain biopsy material derived from MS patients and controls. Furthermore, we addressed a possible monocyte dysfunction in MS and analyzed migratory properties of monocyte subsets using human brain microvascular endothelial cells. Our ex vivo studies demonstrated that CD16(+) monocyte subpopulations are functional but numerically reduced in the peripheral blood of MS patients. CD16(+) monocytes with an intermediate-like phenotype were found to be enriched in CSF and dominated the CSF monocyte population under noninflammatory conditions. In contrast, an inversed CD16(+) to CD16 -: CSF monocyte ratio was observed in MS patients with relapsing-remitting disease. Newly infiltrating, hematogenous CD16(+) monocytes were detected in a perivascular location within active MS lesions, and CD16(+) monocytes facilitated CD4(+) T cell trafficking in a blood -: brain barrier model. Our findings support an important role of CD16(+) monocytes in the steady-state immune surveillance of the CNS and suggest that CD16(+) monocytes shift to sites of inflammation and contribute to the breakdown of the blood-brain barrier in CNS autoimmune diseases.
单核细胞是一类异质性的主要免疫效应细胞群体。根据低亲和力FcγRIII的表达情况，至少可区分出三个不同的亚群：CD14(++)CD16 - ：经典单核细胞，CD14(++)CD16(+)中间单核细胞，以及CD14(+)CD16 ++ ：非经典单核细胞。虽然CD16 - ：经典单核细胞被认为是多发性硬化症（MS）的关键参与者，但关于CD16(+)单核细胞及其在该疾病中的作用知之甚少。在本研究中，我们检测了来自MS患者和对照的外周血、脑脊液（CSF）及脑活检材料中单核细胞亚群的频率和表型。此外，我们探讨了MS中可能存在的单核细胞功能障碍，并使用人脑微血管内皮细胞分析了单核细胞亚群的迁移特性。我们的体外研究表明，CD16(+)单核细胞亚群具有功能，但在MS患者外周血中的数量减少。发现具有中间样表型的CD16(+)单核细胞在CSF中富集，并且在非炎症条件下主导CSF单核细胞群体。相反，在复发缓解型疾病的MS患者中观察到CD16(+)与CD16 - ：CSF单核细胞比例倒置。在活动性MS病变的血管周围位置检测到新浸润的血源性CD16(+)单核细胞，并在血脑屏障模型中发现CD16(+)单核细胞促进CD4(+) T细胞迁移。我们的研究结果支持CD16(+)单核细胞在中枢神经系统稳态免疫监视中的重要作用，并表明CD16(+)单核细胞转移至炎症部位并参与中枢神经系统自身免疫性疾病中血脑屏障的破坏。
