Läderach Fabienne, Piteros Ioannis, Fennell Éanna, Bremer Elena, Last Mette, Schmid Sandra, Rieble Lisa, Campbell Caroline, Ludwig-Portugall Isis, Bornemann Lea, Gruhl Alexander, Eulitz Klaus, Gueguen Paul, Mietz Juliane, Müller Anne, Pezzino Gaetana, Schmitz Jürgen, Ferlazzo Guido, Mautner Josef, Münz Christian
Viral Immunobiology, Institute of Experimental Immunology, University of Zürich, Zürich, Switzerland.
School of Medicine, Bernal Institute, Health Research Institute, Limerick Digital Cancer Research Centre, University of Limerick, Limerick, Ireland.
Nature. 2025 Aug 6. doi: 10.1038/s41586-025-09378-0.
Epidemiological data have identified Epstein-Barr virus (EBV) infection as the main environmental risk factor for multiple sclerosis, the predominant autoimmune disease of the central nervous system (CNS). However, how EBV infection initiates multiple sclerosis pathogenesis remains unclear. Here we demonstrate that EBV expands oligoclonal T-betCXCR3 B cells that home to the CNS in humanized mice. Effector memory CD8 T cells and CD4 T1 cells as well as CD4 T17 cells co-migrate to the brain of EBV-infected humanized mice. T-betCXCR3 B cells can colonize submeningeal brain regions in the absence of other lymphocytes and attract T cells. Depletion of B cells with rituximab or blocking of CXCR3 significantly decreases lymphocyte infiltration into the CNS. Thus, we suggest that symptomatic primary EBV infection generates B cell subsets that gain access to the CNS, attract T cells and thereby initiate multiple sclerosis.
流行病学数据已确定爱泼斯坦-巴尔病毒（EBV）感染是多发性硬化症的主要环境风险因素，多发性硬化症是中枢神经系统（CNS）最主要的自身免疫性疾病。然而，EBV感染如何引发多发性硬化症的发病机制仍不清楚。在此，我们证明EBV在人源化小鼠中扩增了归巢至中枢神经系统的寡克隆T-betCXCR3 B细胞。效应记忆CD8 T细胞、CD4 T1细胞以及CD4 T17细胞共同迁移至EBV感染的人源化小鼠的大脑。T-betCXCR3 B细胞可在无其他淋巴细胞的情况下定殖于脑膜下脑区并吸引T细胞。使用利妥昔单抗清除B细胞或阻断CXCR3可显著减少淋巴细胞向中枢神经系统的浸润。因此，我们认为有症状的原发性EBV感染产生了能够进入中枢神经系统、吸引T细胞从而引发多发性硬化症的B细胞亚群。
