Abstract
Multiple sclerosis (MS) is a chronic central nervous system inflammatory disease that leads to demyelination and neurodegeneration. The third trimester of pregnancy, which is characterized by high levels of estrogens, has been shown to be associated with reduced relapse rates compared with the rates before pregnancy. These effects could be related to the anti-inflammatory properties of estrogens, which orchestrate the reshuffling of the immune system toward immunotolerance to allow for fetal growth. The action of these hormones is mediated by the transcriptional regulation activity of estrogen receptors (ERs). Estrogen levels and ER expression define a specific balance of immune cell types. In this review, we explore the role of estradiol (E2) and ERs in the adaptive immune system, with a focus on estrogen-mediated cellular, molecular, and epigenetic mechanisms related to immune tolerance and neuroprotection in MS. The epigenome dynamics of immune systems are described as key molecular mechanisms that act on the regulation of immune cell identity. This is a completely unexplored field, suggesting a future path for more extensive research on estrogen-induced coregulatory complexes and molecular circuitry as targets for therapeutics in MS.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), and is characterized by the infiltration of T lymphocytes, B lymphocytes, macrophages, and natural killer (NK) cells, as well as demyelination and axonal damage [1]
We recently demonstrated that FOXP3 is promoted in human peripheral blood mononuclear cells (PBMCs) upon stimulation with pregnancy levels of estradiol from Th17 cells undergoing estradiol potentiates the the suppressive function of Treg undergoing polarization polarizationininvitro vitro[90]
No serious side effects were observed; there were neither significant alterations in any laboratory measures including sexual hormone levels [153]. These promising preliminary results led to a larger phase 2 trial [154] that enrolled 164 female MS patients, who were treated with glatiramer acetate (GA), an immunomodulating drug used as a first line therapy for MS, and E3 as an add-on therapy compared with GA alone
Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), and is characterized by the infiltration of T lymphocytes, B lymphocytes, macrophages, and natural killer (NK) cells, as well as demyelination and axonal damage [1]. In the CNS, macrophages and activated CD4+ and CD8+ T cells attack myelin components and produce cytokines and chemokines that recruit other autoreactive cells from peripheral blood. They activate B cells, which mature to antibody-producing plasma cells; induce, maintain, and reactivate CD4+ T cells; and produce proinflammatory cytokines. In MS patients, estradiol regulates immune responses by regulating the expression and release of inflammatory and anti-inflammatory cytokines, leading to a regulatory immune response [27] These data suggest a potential role of estrogens in MS, few clinical trials have been completed so far. We discuss the current knowledge of the relationship between estrogens, the immune system, and MS from a cellular, molecular, and epigenetic point of view
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