Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis

J Neuroinflammation. 2017 Jul 24;14(1):148. doi: 10.1186/s12974-017-0924-4.


Background: MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS).

Methods: MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P1 receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro.

Results: FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220+ B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs.

Conclusions: The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.

Keywords: B cells; EAE; FTY720; Fingolimod; Multiple sclerosis; TLO.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / metabolism
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology
  • Calcium-Binding Proteins / metabolism
  • Cell Aggregation / drug effects
  • Central Nervous System / pathology
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / blood
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy*
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Enzyme-Linked Immunospot Assay
  • Female
  • Fingolimod Hydrochloride / therapeutic use*
  • Flow Cytometry
  • Freund's Adjuvant / toxicity
  • Immunosuppressive Agents / therapeutic use*
  • Lymph Nodes / pathology
  • Mice
  • Myelin Basic Protein / immunology
  • Myelin Basic Protein / toxicity
  • Myelin Proteolipid Protein / immunology
  • Myelin Proteolipid Protein / toxicity
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / toxicity
  • Spleen / pathology
  • Time Factors


  • Antigens, CD19
  • Cacybp protein, mouse
  • Calcium-Binding Proteins
  • Immunosuppressive Agents
  • MP4 protein, chimeric
  • Myelin Basic Protein
  • Myelin Proteolipid Protein
  • Recombinant Fusion Proteins
  • Freund's Adjuvant
  • Fingolimod Hydrochloride