Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression
Takashi Matsushita, … , Manabu Fujimoto, Thomas F. Tedder
Takashi Matsushita, … , Manabu Fujimoto, Thomas F. Tedder
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3420-3430. https://doi.org/10.1172/JCI36030.
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Research Article

Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression

Abstract

EAE is a mouse T cell–mediated autoimmune disease of the CNS used to model the human condition MS. The contributions of B cells to EAE initiation and progression are unclear. In this study, we have shown that EAE disease initiation and progression are differentially influenced by the depletion of B cells from mice with otherwise intact immune systems. CD20 antibody–mediated B cell depletion before EAE induction substantially exacerbated disease symptoms and increased encephalitogenic T cell influx into the CNS. Increased symptom severity resulted from the depletion of a rare IL-10–producing CD1dhiCD5+ regulatory B cell subset (B10 cells), since the adoptive transfer of splenic B10 cells before EAE induction normalized EAE in B cell–depleted mice. While transfer of regulatory B10 cells was maximally effective during early EAE initiation, they had no obvious role during disease progression. Rather, B cell depletion during EAE disease progression dramatically suppressed symptoms. Specifically, B cells were required for the generation of CD4+ T cells specific for CNS autoantigen and the entry of encephalitogenic T cells into the CNS during disease progression. These results demonstrate reciprocal regulatory roles for B cells during EAE immunopathogenesis. The therapeutic effect of B cell depletion for the treatment of autoimmunity may therefore depend on the relative contributions and the timing of these opposing B cell activities during the course of disease initiation and pathogenesis.

Authors

Takashi Matsushita, Koichi Yanaba, Jean-David Bouaziz, Manabu Fujimoto, Thomas F. Tedder

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Figure 8

Regulatory CD1dhiCD5+ B10 cells suppress disease symptoms in EAE.

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Regulatory CD1dhiCD5+ B10 cells suppress disease symptoms in EAE. (A...
(A) Splenic CD1dhiCD5+ or non-CD1dhiCD5+ B cells were purified from naive mice or mice with EAE (day 10) by cell sorting. RNA was isolated from purified splenic B cells. Values represent relative mean IL-10 transcripts normalized to GAPDH transcript levels (mean ± SEM, n ≥ 6 mice per group) as quantified by real-time PCR analysis. Significant differences between sample means are indicated; *P < 0.05, **P < 0.01. Similar results were obtained in at least 2 independent experiments. (B) Representative results showing splenic CD19+ B cells from Cd20–/– mice sorted into regulatory CD1dhiCD5+ and nonregulatory CD1dhiCD5+ B cell subsets. (C–E) Wild-type recipient mice that had been treated with CD20 or control mAb 7 days before MOG immunization (arrowheads) were given either purified CD1dhiCD5+ or non-CD1dhiCD5+ B cells from (C) naive Cd20–/– mice 2 days before immunization, (D) naive Il10–/–Cd20–/– mice 2 days before immunization, or (E) naive Cd20–/– mice 14 days after immunization. (F) Wild-type recipient mice treated with CD20 or control mAb 14 days after MOG immunization (arrowhead) were also given purified CD1dhiCD5+ B cells from naive Cd20–/– mice. Values represent (mean ± SEM) from more than 5 mice in each group, with similar results obtained in 2 independent experiments. Significant differences between the means of EAE clinical scores are indicated: *P < 0.05 (CD20 mAb treated plus CD1dhiCD5 versus mAb treated); **P < 0.05 (CD20 mAb treated plus CD1dhiCD5 versus CD20 mAb treated plus non–CD1dhiCD5+ treated); †P < 0.05 (CD20 mAb treated plus CD1dhiCD5 versus control mAb treated).