title: 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.affiliation: Neuroimmunology Research, Portland VA Medical Center, Portland, OR 97239, USA.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Bodhankar
authors.forename: Chunhe
authors.initials: C
authors.lastname: Wang
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D060890:B7-H1 Antigen; D018956:CD5 Antigens / Q000276:immunology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004958:Estradiol / Q000276:immunology; D004967:Estrogens / Q000276:immunology*; D005260:Female; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000172:deficiency / Q000276:immunology; D013154:Spleen / Q000276:immunology
chemical_list: D055610:Antigens, CD1d; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D018956:CD5 Antigens; C526879:Cd1d1 protein, mouse; C498919:Cd274 protein, mouse; D004967:Estrogens; D008562:Membrane Glycoproteins; D010455:Peptides; D004958:Estradiol