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(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.

• Authors: Sheetal Bodhankar, Chunhe Wang, Arthur A Vandenbark, Halina Offner
• Journal: European journal of immunology (Eur J Immunol) Vol. 41 Issue 4 Pg. 1165-75 (Apr 2011) ISSN: 1521-4141 [Electronic] Germany
• PMID: 21413005 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antigens, CD1d
• B7-1 Antigen
• B7-H1 Antigen
• CD5 Antigens
• Cd1d1 protein, mouse
• Cd274 protein, mouse
• Estrogens
• Membrane Glycoproteins
• Peptides
• Estradiol

Topics

• Animals
• Antigens, CD1d (immunology)
• B-Lymphocytes (immunology)
• B7-1 Antigen (immunology)
• B7-H1 Antigen
• CD5 Antigens (immunology)
• Cells, Cultured
• Encephalomyelitis, Autoimmune, Experimental (immunology)
• Estradiol (immunology)
• Estrogens (immunology)
• Female
• Membrane Glycoproteins (deficiency, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Peptides (deficiency, immunology)
• Spleen (immunology)