Estrogen-induced protection against experimental autoimmune encephalomyelitis is abrogated in the absence of B cells

Neuroimmunology Research, Portland VA Medical Center, Portland, OR 97239, USA.
European Journal of Immunology (Impact Factor: 4.03). 04/2011; 41(4):1165-75. DOI: 10.1002/eji.201040992
Source: PubMed


Increased remissions in multiple sclerosis (MS) during pregnancy suggest that elevated levels of sex steroids exert immunoregulatory activity. Estrogen (E2=17β-estradiol) protects against experimental autoimmune encephalomyelitis (EAE), but the cellular basis for E2-induced protection remains unclear. Studies demonstrate that depletion of B cells prior to induction of EAE exacerbates disease severity, implicating regulatory B cells. We thus evaluated pathogenic and E2-induced protective mechanisms in B-cell-deficient (μMT(-/-)) mice. EAE-protective effects of E2 were abrogated in μMT(-/-) mice, with no reduction in disease severity, cellular infiltration or pro-inflammatory factors in the central nervous system compared to untreated controls. E2 treatment of WT mice selectively upregulated expression of PD-L1 on B cells and increased the percentage of IL-10-producing CD1d(high) CD5(+) regulatory B cells. Upregulation of PD-L1 was critical for E2-mediated protection since E2 did not inhibit EAE in PD-L1(-/-) mice. Direct treatment of B cells with E2 significantly reduced proliferation of MOG(35-55)-specific T cells that required estrogen receptor-α (ERα). These results demonstrate, for the first time, a requirement for B cells in E2-mediated protection against EAE involving direct E2 effects on regulatory B cells mediated through ERα and the PD-1/PD-L1 negative co-stimulatory pathway. E2-primed B cells may represent an important regulatory mechanism in MS and have strong implications for women receiving current MS therapies that cause B-cell depletion.

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Available from: Arthur A Vandenbark
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    • "E2 has been proved to protect mice from EAE, while this protection was abrogated in B cell-deficient (muMT) mice [60]. E2 treatment upregulated the expression of PD-L1 on B cells and increased the numbers of IL-10-producing CD1d hi CD5 + B cells [60]. In addition, E2 treatment in PD-L1 À/À mice was also ineffective, and transfer of PD-L1 À/À B cells to muMT mice could not restore the protection observed in WT mice [57]. "
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    • "We further ascertained whether differences in surface expression of CD1d hi CD5 + on B cells (Bregs) in the PD-L1 −/− or PD-L2 −/− mice as compared to WT mice might reflect the differences in protection in these strains, after the transfer of Breg cells. We assessed the expression of a recently characterized regulatory B-cell sub-population, known as the CD1d hi CD5 + CD19 + Bregs (Bodhankar et al., 2011) which is known to effectively downregulate T-cell activation by virtue of their IL-10 production (Yanaba et al., 2008). We determined the CD1d hi CD5 + expression (Figure 8C) and IL-10-secretion by B cells (Figure 8D). "
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    • "Due to the importance of the PD-1/PD-L system in MS, therapeutic strategies targeting PD- 1/PD-L1 interactions can be envisioned as an immunosuppressive treatment for MS patients. For example, estrogen has been shown to effectively protect against EAE through upregulating PD-L1 expression on B cells and increase the amount of IL-10-producing regulatory B cells (Bodhankar et al., 2011). It also induces B-celldependent up-regulation of PD-1 on CD4 + Foxp3 + Tregs, which provide further protection against EAE (Bodhankar et al., 2012). "
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