Jelcic Ivan, Naghavian Reza, Fanaswala Imran, Macnair Will, Esposito Cinzia, Calini Daniela, Han Yanan, Marti Zoe, Raposo Catarina, Sarabia Del Castillo Jacobo, Oldrati Pietro, Erny Daniel, Kana Veronika, Zheleznyakova Galina, Al Nimer Faiez, Tackenberg Björn, Reichen Ina, Khademi Mohsen, Piehl Fredrik, Robinson Mark D, Jelcic Ilijas, Sospedra Mireia, Pelkmans Lucas, Malhotra Dheeraj, Reynolds Richard, Jagodic Maja, Martin Roland
Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland; Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Neuroimmunology and MS Research Section (NIMS), Neurology Clinic, University of Zurich, University Hospital Zurich, 8091 Zurich, Switzerland.
Cell Rep Med. 2025 Mar 18;6(3):102027. doi: 10.1016/j.xcrm.2025.102027.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Self-peptide-dependent autoproliferation (AP) of B and T cells is a key mechanism in MS. Here, we show that pro-inflammatory B-T cell-enriched cell clusters (BTECs) form during AP and mirror features of a germinal center reaction. T-bet+CXCR3+ B cells are the main cell subset amplifying and sustaining their counterpart Th1 cells via interferon (IFN)-γ and are present in highly inflamed meningeal tissue. The underlying B cell activation signature is reflected by epigenetic modifications and receptor-ligand interactions with self-reactive T cells. AP+ CXCR3+ B cells show marked clonal evolution from memory to somatically hypermutated plasmablasts and upregulation of IFN-γ-related genes. Our data underscore a key role of T-bet+CXCR3+ B cells in the pathogenesis of MS in both the peripheral immune system and the CNS compartment, and thus they appear to be involved in both early relapsing-remitting disease and the chronic stage.
多发性硬化症（MS）是一种中枢神经系统（CNS）的自身免疫性疾病。B细胞和T细胞的自身肽依赖性自身增殖（AP）是MS的关键机制。在此，我们表明，在AP过程中会形成富含促炎B-T细胞的细胞簇（BTECs），其反映了生发中心反应的特征。T-bet+CXCR3+B细胞是主要的细胞亚群，通过干扰素（IFN）-γ扩增并维持其对应的Th1细胞，且存在于高度炎症的脑膜组织中。潜在的B细胞激活特征通过表观遗传修饰以及与自身反应性T细胞的受体-配体相互作用得以体现。AP+CXCR3+B细胞显示出从记忆细胞到体细胞超突变浆母细胞的显著克隆进化以及IFN-γ相关基因的上调。我们的数据强调了T-bet+CXCR3+B细胞在MS发病机制中在外周免疫系统和中枢神经系统区域的关键作用，因此它们似乎参与了早期复发缓解型疾病以及慢性阶段。
