Klinikum rechts der Isar, Department of Neurology, Technical University of Munich, 81675 Munich, Germany.
Klinikum rechts der Isar, Institute for Experimental Neuroimmunology, Technical University of Munich, 81675 Munich, Germany.
Brain. 2021 Jul 28;144(6):1697-1710. doi: 10.1093/brain/awab093.
Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic multiple sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of multiple sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T-cell and B-cell receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of α4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of α4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with α4 integrin-sufficient T cells. B cell-conditional ablation of α4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with α4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20% of B cells in organized meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in multiple sclerosis.
脑膜 B 淋巴细胞聚集体已在慢性多发性硬化症患者的尸检材料中描述。脑膜 B 细胞聚集体的存在与疾病恶化相关。然而，这些脑膜 B 细胞聚集体的功能作用尚不清楚。在这里，我们使用多发性硬化症的小鼠模型，即自发的视神经脊髓炎模型，该模型基于髓鞘少突胶质细胞糖蛋白特异性 T 细胞和 B 细胞受体的双转基因表达，表明脑膜 B 细胞聚集体的形成依赖于抗原特异性 T 细胞表达 α4 整合素。在视神经脊髓炎小鼠中，T 细胞条件性遗传敲除 α4 整合素会损害脑膜 B 细胞聚集体的形成，令人惊讶的是，与 α4 整合素足够的 T 细胞相比，视神经脊髓炎小鼠的疾病发病率更高。在视神经脊髓炎小鼠中，B 细胞条件性敲除 α4 整合素导致脑膜 B 细胞聚集体的完全缺失，而缺乏 α4 整合素的 B 细胞的视神经脊髓炎小鼠比常规的视神经脊髓炎小鼠遭受更高的疾病负担。虽然在疾病发作后用抗 CD20 抗体进行系统性耗尽 B 细胞不能有效地减少脑膜 B 细胞聚集体，而不显著调节疾病进展，但用抗 CD19 嵌合抗原受体-T 细胞治疗消除了脑膜 B 细胞聚集体，并加剧了视神经脊髓炎小鼠的临床疾病。由于约 20%的组织化脑膜 B 细胞聚集体中的 B 细胞产生 IL-10 或 IL-35，我们提出脑膜 B 细胞聚集体也可能对相邻脊髓白质的免疫病理学具有免疫调节功能。在设计针对多发性硬化症的脑膜 B 细胞聚集体的高效治疗方法时，需要考虑脑膜 B 细胞聚集体的免疫调节功能。
