Abstract
BackgroundMP4-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).MethodsMP4-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.ResultsFTY720 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.ConclusionsThe data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.
Highlights
myelin basic protein (MBP)-proteolipid protein (PLP) fusion protein (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
We have introduced a B cell-/ antibody-dependent model of experimental autoimmune encephalomyelitis (EAE), which is based upon active immunization of C57BL/6 (B6) mice with MBP-PLP fusion protein (MP4), a fusion protein of myelin basic protein (MBP) and proteolipid protein (PLP) [10]
EAE onset in all treated cohorts was 19.05 ± 3.20 days post immunization, and treatment started at a mean EAE score of 2.19 ± 0.19 in the FTY720 group compared to a mean EAE score of 2.29 ± 0.19 in the vehicle group (p = 0.90)
Summary
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 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). CNS-reactive B cells were detected in the peripheral blood of MS patients [7] and clonally expanded B cells were found in the CNS and cerebrospinal fluid (CSF) [8] Along these lines, oligoclonal bands (OCBs) indicate intrathecal antibody synthesis [2] and antibody depositions with concurrent complement activation represent the most frequently observed pattern of demyelination in MS brain lesions [9]. Drug administration during the chronic stage of the disease remained ineffective on these parameters, but displayed an inhibitory effect on B cell aggregate transformation into TLOs
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