Therapeutic Immune Design, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:02, 171 76, Stockholm, Sweden.
Institute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, Ludwig-Maximilians-Universität München, Großhaderner Str. 9, 821 52, Planegg-Martinsried, Germany.
J Autoimmun. 2019 Aug;102:38-49. doi: 10.1016/j.jaut.2019.04.013. Epub 2019 May 1.
Autoreactive CD4 T-cells are believed to be a main driver of multiple sclerosis (MS). Myelin oligodendrocyte glycoprotein (MOG) is considered an autoantigen, yet doubted in recent years. The reason is in part due to low frequency and titers of MOG autoantibodies and the challenge to detect MOG-specific T-cells. In this study we aimed to analyze T-cell reactivity and frequency utilizing a novel method for detection of antigen-specific T-cells with bead-bound MOG as stimulant. Peripheral blood mononuclear cells (PBMCs) from natalizumab treated persons with MS (n = 52) and healthy controls (HCs) (n = 24) were analyzed by IFNγ/IL-22/IL-17A FluoroSpot. A higher number of IFNγ (P = 0.001), IL-22 (P = 0.003), IL-17A (P < 0.0001) as well as double and triple cytokine producing MOG-specific T-cells were detected in persons with MS compared to HCs. Of the patients, 46.2-59.6% displayed MOG-reactivity. Depletion of CD4 T-cells or monocytes or blocking HLA-DR completely eliminated the MOG specific response. Anti-MOG antibodies did not correlate with T-cell MOG-responses. In conclusion, we present a sensitive method to detect circulating autoreactive CD4 T-cells producing IFNγ, IL-22 or IL-17A using MOG as a model antigen. Further, we demonstrate that MOG-specific T-cells are present in approximately half of persons with MS.
自身反应性 CD4 T 细胞被认为是多发性硬化症 (MS) 的主要驱动因素。髓鞘少突胶质细胞糖蛋白 (MOG) 被认为是自身抗原，但近年来受到质疑。原因部分是由于 MOG 自身抗体的频率和滴度低，以及检测 MOG 特异性 T 细胞的挑战。在这项研究中，我们旨在利用一种新的方法来分析 T 细胞反应性和频率，该方法使用珠结合的 MOG 作为刺激物来检测抗原特异性 T 细胞。利用 IFNγ/IL-22/IL-17A FluoroSpot 分析纳昔单抗治疗的 MS 患者（n=52）和健康对照者（HCs）（n=24）的外周血单核细胞（PBMCs）。与 HCs 相比，MS 患者中检测到更多的 IFNγ（P=0.001）、IL-22（P=0.003）、IL-17A（P<0.0001）以及双和三细胞因子产生的 MOG 特异性 T 细胞。在这些患者中，46.2-59.6% 显示出 MOG 反应性。耗尽 CD4 T 细胞或单核细胞或阻断 HLA-DR 可完全消除 MOG 特异性反应。抗 MOG 抗体与 T 细胞 MOG 反应之间没有相关性。总之，我们提出了一种灵敏的方法，使用 MOG 作为模型抗原来检测循环自身反应性 CD4 T 细胞产生 IFNγ、IL-22 或 IL-17A。此外，我们证明 MOG 特异性 T 细胞存在于大约一半的 MS 患者中。
