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

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^highCD5⁺ 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.