Huseby Kelcher April M, Atanga Pascal A, Gamez Jeffrey D, Cumba Garcia Luz M, Teclaw Stephanie J, Pavelko Kevin D, Macura Slobodan I, Johnson Aaron J
Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA.
Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA.
FASEB J. 2017 Jun;31(6):2267-2275. doi: 10.1096/fj.201601055R. Epub 2017 Feb 10.
Brain atrophy is a common feature of numerous neurologic diseases in which the role of neuroinflammation remains ill-defined. In this study, we evaluated the contribution of major histocompatibility complex class I molecules to brain atrophy in Theiler's murine encephalomyelitis virus (TMEV)-infected transgenic FVB mice that express the D class I molecule. FVB/D and wild-type FVB mice were evaluated for changes in neuroinflammation, virus clearance, neuropathology, and development of brain atrophy T2-weighted MRI and subsequent 3-dimensional volumetric analysis. Significant brain atrophy and hippocampal neuronal loss were observed in TMEV-infected FVB/D mice, but not in wild-type FVB mice. Brain atrophy was observed at 1 mo postinfection and persisted through the 4-mo observation period. Of importance, virus-infected FVB/D mice elicited a strong CD8 T-cell response toward the immunodominant D-restricted TMEV-derived peptide, VP2, and cleared TMEV from the CNS. In addition, immunofluorescence revealed CD8 T cells near virus-infected neurons; therefore, we hypothesize that class I restricted CD8 T-cell responses promote development of brain atrophy. This model provides an opportunity to analyze the contribution of immune cells to brain atrophy in a system where persistent virus infection and demyelination are not factors in long-term neuropathology.-Huseby Kelcher, A. M., Atanga, P. A., Gamez, J. D., Cumba Garcia, L. M., Teclaw, S. J., Pavelko, K. D., Macura, S. I., Johnson. A. J. Brain atrophy in picornavirus-infected FVB mice is dependent on the H-2D class I molecule.
脑萎缩是众多神经疾病的常见特征，其中神经炎症的作用仍不明确。在本研究中，我们评估了主要组织相容性复合体I类分子对感染泰勒氏鼠脑脊髓炎病毒（TMEV）的转基因FVB小鼠脑萎缩的影响，这些小鼠表达D类I分子。通过T2加权磁共振成像（MRI）及随后的三维容积分析，对FVB/D和野生型FVB小鼠的神经炎症变化、病毒清除、神经病理学及脑萎缩发展情况进行了评估。在感染TMEV的FVB/D小鼠中观察到显著的脑萎缩和海马神经元丢失，而野生型FVB小鼠未出现此现象。感染后1个月即观察到脑萎缩，并在4个月的观察期内持续存在。重要的是，病毒感染的FVB/D小鼠对免疫显性的D限制性TMEV衍生肽VP2产生了强烈的CD8 T细胞反应，并从中枢神经系统清除了TMEV。此外，免疫荧光显示病毒感染神经元附近有CD8 T细胞；因此，我们推测I类限制性CD8 T细胞反应促进了脑萎缩的发展。该模型为在一个长期神经病理学中不存在持续性病毒感染和脱髓鞘因素的系统中分析免疫细胞对脑萎缩的作用提供了机会。-赫西·凯尔彻，A.M.，阿坦加，P.A.，加梅兹，J.D.，昆巴·加西亚，L.M.，特克劳，S.J.，帕维尔科，K.D.，马库拉，S.I.，约翰逊，A.J. 微小核糖核酸病毒感染的FVB小鼠脑萎缩依赖于H-2D类I分子
