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Review
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The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View

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Review

The Adaptive Immune System in Multiple Sclerosis: An Estrogen-Mediated Point of View

Alessandro Maglione et al. Cells.

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.

Keywords: adaptive immune system; epigenome; estrogen receptors; estrogens; multiple sclerosis; pregnancy.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Estradiol levels in the bloodstream vary throughout a woman’s lifespan. The mean value during childhood is 200 pg/mL. During fertility age, the menstrual cycle range is 100–400 pg/mL. The pregnancy condition (highlighted in pink) is characterized by a huge increase in levels of circulating estradiol from the first trimester to delivery, with a range of 2000–15,000 pg/mL. During menopause, the level of estrogens drops drastically to <100 pg/mL. Data retrieved from Watson et al., 2010 [36].
Figure 2
Figure 2
The three main different isoforms of ERα are presented: the full-length 66 kDa ERα (ERα66), the AF-1 domain-truncated 46 kDa variant of ERα (ERα46), and a 36 kDa ERα variant (ERα36) that lacks both AF-1 and AF-2 domains [43,44,45]. The relative protein levels in different immune system cells are indicated by ++, +, or ND (not detected) [61,65].
Figure 3
Figure 3
ERα and ERβ expression in the immune system. The bar plots represent gene expression data of the human genes ESR1 and ESR2, which encode for ERα and ERβ, respectively. Data were retrieved from the Database of Immune Cell expression, expression quantitative trait loci (eQTL), and epigenomics (DICE) [67]. RNA-Seq data are normalized between samples and expressed in transcripts per million (TPM). Data were generated from 13 immune cell types from 91 healthy subjects. The cell types include: three innate immune cell types (CD14high CD16− classical monocytes, CD14− CD16+ non-classical monocytes, and CD56dim CD16+ natural killer (NK) cells); four adaptive immune cell types that have not encountered their cognate antigen in the periphery (naive B cells, naive CD4+ T cells, naive CD8+ T cells, and naive Treg cells); six differentiated T cell subsets (Th1, Th1/17, Th17, Th2, follicular helper T cells (TFH), and memory Treg cells); and two ex vivo activated cell types (naive CD4+ and CD8+ T cells).
Figure 4
Figure 4
E2 regulates cytokine production in CD4+ T cells. As estrogen levels increase, IFN-γ and TNF-α production decreases, while IL-10 secretion increases.
Figure 5
Figure 5
A model of ERα-dependent modulation of nuclear organization of chromatin in T helper cells. Estrogens participate in the mechanisms of transcriptional regulation through the binding of ERα at regulatory regions, thereby influencing the phenotype of T helper cells. Estrogens at normal levels promote the binding and activation of Th17 lineage-specific TFs (e.g., RORC), whereas estrogens at pregnancy levels bind preferentially to Treg lineage-specific TFs, thus inhibiting RORC and promoting FOXP3 transcriptional activation [90]. ERα may participate with TFs that are specific for Th17 and Treg lineages in chromatin remodeling in these cells, although the mechanisms are still unclear.

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