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

Sheetal Bodhankar, Chunhe Wang, Arthur A. Vandenbark, Halina Offner

Research output: Contribution to journalArticle

57 Scopus citations

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 CD1dhighCD5+ 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 MOG35-55-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.

Original languageEnglish (US)
Pages (from-to)1165-1175
Number of pages11
JournalEuropean Journal of Immunology
Volume41
Issue number4
DOIs
StatePublished - Apr 1 2011

    Fingerprint

Keywords

  • EAE
  • Estrogen
  • MS
  • Regulatory B cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this