Formation and immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity

Meike Mitsdoerffer, Giovanni Di Liberto, Sarah Dötsch, Christopher Sie, Ingrid Wagner, Monika Pfaller, Mario Kreutzfeldt, Simon Fräßle, Lilian Aly, Benjamin Knier, Dirk H. Busch, Doron Merkler, Thomas Korn

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)1697-1710
Number of pages14
JournalBrain
Volume144
Issue number6
DOIs
StatePublished - 1 Jun 2021

Keywords

  • B cell
  • CAR T cell
  • experimental autoimmune encephalomyelitis
  • meningeal inflammation
  • multiple sclerosis

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