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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    • "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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    ABSTRACT: The term regulatory B cells (B regs) is ascribed to a heterogeneous population of B cells with the function of suppressing inflammatory responses. They have been described mainly during the last decade in the context of different immune-mediated diseases. Most of the work on B regs has been focused on IL-10-producing B cells. However, B cells can exert regulatory functions independently of IL-10 production. Here we discuss the phenotypes, development and effector mechanisms of B regs and advances in their role in autoimmunity, infections and cancer.
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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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    ABSTRACT: Immune responses in the central nervous system (CNS), which involve both resident glial cells and infiltrating peripheral immune cells, play critical roles in the progress of brain injuries and neurodegeneration. To avoid inflammatory damage to the compromised brain, the immune cell activities in the CNS are controlled by a plethora of chemical mediators and signal transduction cascades, such as inhibitory signaling through programed death-1 (PD-1) and programed death ligand (PD-L) interactions. An increasing number of recent studies have highlighted the importance of PD-1/PD-L pathway in immune regulation in CNS disorders such as ischemic stroke, multiple sclerosis, and Alzheimer's disease. Here, we review the current knowledge of the impact of PD-1/PD-L signaling on brain injury and neurodegeneration. An improved understanding of the function of PD-1/PD-L in the cross-talk between peripheral immune cells, CNS glial cells, and non-immune CNS cells is expected to shed further light on immunomodulation and help develop effective and safe immunotherapies for CNS disorders.
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