2. Academic Validation
  3. Cognate interaction-dependent pathogenicity of meningeal B cells drives neuroinflammation relapse

Cognate interaction-dependent pathogenicity of meningeal B cells drives neuroinflammation relapse

  • Immunity. 2025 Sep 9;58(9):2256-2270.e8. doi: 10.1016/j.immuni.2025.06.016.
Yan Wang 1,  Di Xu 2,  Shaorui Liu 1,  Haoyang Li 1,  Yinsheng Wang 1,  Hui Li 1,  Heping Xu 3,  Danyang He 4
Affiliations

Affiliations

  • 1 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Laboratory of Systems Immunology, School of Medicine, Westlake University, Hangzhou 310024, Zhejiang, China.
  • 2 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Laboratory of Neuroimmunology, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China.
  • 3 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Laboratory of Systems Immunology, School of Medicine, Westlake University, Hangzhou 310024, Zhejiang, China. Electronic address: xuheping@westlake.edu.cn.
  • 4 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Laboratory of Neuroimmunology, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China. Electronic address: hedanyang@westlake.edu.cn.
PMID: 40669468 DOI: 10.1016/j.immuni.2025.06.016
Abstract

B cells are central drivers of central nervous system (CNS) autoimmune disorders, including multiple sclerosis (MS). Although the brain meninges normally maintain a stringently non-self-reactive B cell repertoire, how disruption of this local immune tolerance contributes to pathology remains unclear. Here, we demonstrated that autoreactive B cells at the brain border accelerated neuroinflammation by directly engaging encephalitogenic T cells. Intracisterna magna injections, used to selectively manipulate meningeal B cell populations in the 2D2 transfer experimental autoimmune encephalomyelitis (EAE) model, revealed that autoreactive B-T interactions in the leptomeninges amplified a local pro-inflammatory loop, promoting neutrophil recruitment and endothelial activation before disease onset. This mechanism required major histocompatibility complex class II (MHC class II) expression by B cells and granulocyte-macrophage colony-stimulating factor (GM-CSF) production by T cells. Furthermore, targeted depletion of brain-localized B cells attenuated EAE relapses in a passive EAE model. These findings establish brain-localized autoreactive B cells as crucial initiators of neuroinflammation and promising therapeutic targets in relapsing MS.

Keywords

B cells; EAE; Endothelial cell; GM-CSF; antigen presentation; autoimmune disease; meninges; neuroinflammation; vascular inflammation.

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