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

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

Author information

1
Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.
2
Institute of Anatomy and Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
3
Core Unit Systems Medicine, University Hospitals of Würzburg, Würzburg, Germany.
4
LIMES Institute, University of Bonn, Bonn, Germany.
5
Department of Neurology, University Hospital Würzburg, Würzburg, Germany.
6
Department of Neurology, University Hospital Essen, Essen, Germany.
7
Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany. stefanie.kuerten@fau.de.
8
Institute of Anatomy and Cell Biology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. stefanie.kuerten@fau.de.

Abstract

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

PMID:
28738885
PMCID:
PMC5525315
DOI:
10.1186/s12974-017-0924-4
[Indexed for MEDLINE]
Free PMC Article

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