Article

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: 4.52). 02/2011; 41(4):1165-75. DOI: 10.1002/eji.201040992
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
86 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pregnancy level of estrogen treatment alleviates the clinical disease progression of EAE.•Estrogen reduces CNS demyelination and limits CNS cell infiltration during established EAE.•Absence of estrogen elicits a high pro-inflammatory environment in spleens.•Estrogen enhanced anti-inflammatory cytokine production in splenocytes from EAE mice.•Estrogen favoring T cell responses in EAE mice to Th2 and Treg through regulation of related transcription factors
    Journal of Neuroimmunology 10/2014; · 2.79 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Frontiers in Cellular Neuroscience 09/2014; 8:271. · 4.18 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Clinical stroke induces inflammatory processes leading to cerebral and splenic injury and profound peripheral immunosuppression. IL-10 expression is elevated during major CNS diseases and limits inflammation in the brain. Recent evidence demonstrated that transfer of IL-10(+) B-cells reduced infarct volume in male C57BL/6J (wild-type, WT) recipient mice when given 24 h prior to or 4 h after middle cerebral artery occlusion (MCAO). The purpose of this study was to determine if passively transferred IL-10(+) B-cells can exert therapeutic and immunoregulatory effects when injected 24 h after MCAO induction in B-cell-sufficient male WT mice. The results demonstrated that IL-10(+) B-cell treated mice had significantly reduced infarct volumes in the ipsilateral cortex and hemisphere and improved neurological deficits vs. Vehicle-treated control mice after 60 min occlusion and 96 h of reperfusion. The MCAO-protected B-cell recipient mice had less splenic atrophy and reduced numbers of activated, inflammatory T-cells, decreased infiltration of T-cells and a less inflammatory milieu in the ischemic hemispheres compared with Vehicle-treated control mice. These immunoregulatory changes occurred in concert with the predominant appearance of IL-10-secreting CD8(+)CD122(+) Treg cells in both the spleen and the MCAO-affected brain hemisphere. This study for the first time demonstrates a major neuroprotective role for IL-10(+) B-cells in treating MCAO in male WT mice at a time point well beyond the ~4 h tPA treatment window, leading to the generation of a dominant IL-10(+)CD8(+)CD122(+) Treg population associated with spleen preservation and reduced CNS inflammation.
    Metabolic Brain Disease 12/2014; · 2.40 Impact Factor

Full-text (2 Sources)

Download
54 Downloads
Available from
May 26, 2014