Multiple sclerosis (MS) is a devastating neurodegenerative disease, characterized by chronic inflammation and demyelination. The incidence of MS is 2-3 times higher in women. However, the relapse rate of MS decreases during late pregnancy and also after treatment with pregnancy levels of estriol (a form of estrogen), leading to a decrease in CNS lesions. Estrogen (E2) is a potent regulator of the immune system and may also act directly on cells of the CNS, including microglia, astrocytes, oligodendrocytes and neurons. Our laboratory has convincingly demonstrated that estrogens exert a pronounced protective effect on clinical and histological disease in the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Immunoregulatory properties of estrogen include dampening proinflammatory cells (e.g. dendritic cells, macrophages and encephalitogenic T cells) and activating Breg and Treg cells. Our goal is to determine the immune-mediated mechanisms that lead to protection of CNS cells (e.g. neurons, oligodendrocytes and microglia, MG). Deciphering the neuroprotective and immunoregulatory effects of estrogen is important for its possible clinical application. Our recent findings demonstrate a requirement for B-cells in E2-mediated protection against EAE involving direct E2 effects on Breg cells mediated through ER? and the PD-1/PD-L negative co-inhibitory pathway. It is likely that chronically activated microglia cause the neuronal and axonal degeneration that occurs in progressive forms of MS. Since the cause of this chronic microglial activation is uncertain, we propose in this application that MG cells represent one major target for regulatory B-cells and other B-cell subsets, whether by secretion of IL-10 or via direct means (cell-cell PD-1/PD-L signaling). In summary, this proposal will contribute new information regarding the potential role of E2 on B-cell subsets in regulating MG activation and protection against EAE.

Public Health Relevance

The beneficial clinical effects on multiple sclerosis (MS) of increased levels of sex hormones, including estrogen (E2) and estriol (E3), during late pregnancy coupled with their successful treatment of experimental autoimmune encephalomyelitis (EAE) in animal models of MS provide a compelling rationale for their use as therapy. The current proposal will provide new insights into the role of E2 in inducing and potentiating regulatory B-cell (Bregs) subsets that can modulate the severity of EAE in mice.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
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Utz, Ursula
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Oregon Health and Science University
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United States
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Meza-Romero, Roberto; Benedek, Gil; Gerstner, Grant et al. (2018) Increased CD74 binding and EAE treatment efficacy of a modified DR?1 molecular construct. Metab Brain Dis :
Seifert, Hilary A; Offner, Halina (2018) The splenic response to stroke: from rodents to stroke subjects. J Neuroinflammation 15:195
Seifert, Hilary A; Benedek, Gil; Nguyen, Ha et al. (2018) Antibiotics protect against EAE by increasing regulatory and anti-inflammatory cells. Metab Brain Dis :
Seifert, Hilary A; Vandenbark, Arthur A; Offner, Halina (2018) Regulatory B cells in experimental stroke. Immunology 154:169-177
Seifert, Hilary A; Benedek, Gil; Nguyen, Ha et al. (2017) Estrogen protects both sexes against EAE by promoting common regulatory cell subtypes independent of endogenous estrogen. Metab Brain Dis 32:1747-1754
Benedek, Gil; Zhang, Jun; Nguyen, Ha et al. (2017) Estrogen protection against EAE modulates the microbiota and mucosal-associated regulatory cells. J Neuroimmunol 310:51-59
Benedek, Gil; Zhang, Jun; Nguyen, Ha et al. (2017) Novel feedback loop between M2 macrophages/microglia and regulatory B cells in estrogen-protected EAE mice. J Neuroimmunol 305:59-67
Benedek, Gil; Meza-Romero, Roberto; Jordan, Kelley et al. (2017) MIF and D-DT are potential disease severity modifiers in male MS subjects. Proc Natl Acad Sci U S A 114:E8421-E8429
Benedek, Gil; Zhang, Jun; Bodhankar, Sheetal et al. (2016) Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis. J Neuroimmunol 293:45-53
Zhang, Jun; Benedek, Gil; Bodhankar, Sheetal et al. (2015) IL-10 producing B cells partially restore E2-mediated protection against EAE in PD-L1 deficient mice. J Neuroimmunol 285:129-36

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