Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 41, Issue 4, Pages 1165-1175Publisher
WILEY
DOI: 10.1002/eji.201040992
Keywords
EAE; Estrogen; MS; Regulatory B cells
Categories
Funding
- NIH [NS45445, NS49210]
- National Multiple Sclerosis Society [RG3405-C-6]
- Biomedical Laboratory R&D Service, Department of Veterans' Affairs
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Increased remissions in multiple sclerosis (MS) during pregnancy suggest that elevated levels of sex steroids exert immunoregulatory activity. Estrogen (E2=17 beta-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 (mu MT-/-) mice. EAE-protective effects of E2 were abrogated in mu MT-/- 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-alpha (ER alpha). 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 ER alpha 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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