Hormonal Influences in Multiple Sclerosis

Shuster, Elizabeth A.

doi:10.1007/978-3-540-73677-6_11

Cited by 15 publications

(14 citation statements)

References 215 publications

(208 reference statements)

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“…Sex difference in prevalence of MS can be attributed to effects of sex hormones, sex chromosomes or a combination of both on the immune system or the central nervous system. The role of circulating sex hormones on the immune system as a potential mechanism of disease discrepancy has been studied extensively (Shuster, 2008, Greer and McCombe, 2011, Voskuhl, 2011), but specifically sex difference in central nervous system demyelination and remyelination is lacking.…”

Section: Introductionmentioning

confidence: 99%

Sex chromosome complement influences functional callosal myelination

Moore¹,

Patel²,

Hannsun³

et al. 2013

Neuroscience

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In addition to androgen differences between males and females, there are genetic differences that are caused by unequal dosage of sex chromosome genes. Using the cuprizone-induced demyelination model, we recently showed that surgical gonadectomy of adult mice resulted in decreased normal myelination and remyelination compared to gonadally intact animals, suggesting a supporting role for sex hormones in the maintenance of myelination. However, inherent sex differences in normal myelination and remyelination persisted even after gonadectomy, with males consistently remyelinating to a lesser extent relative to normal myelination as assayed by axon conduction and immunohistochemistry. This suggests a potential role for the sex chromosome complement in mediating the differential rates of remyelination observed in males and females. The present study focuses on the impact that sex chromosomes might have on these myelination differences. Making use of the four core-genotype \mice and cuprizone-diet induced demyelination/remyelination paradigm, our results demonstrate sex chromosome mediated asymmetry between XX and XY mice. The rate of functional remyelination following cuprizone diet-induced callosal demyelination in four core-genotype mice is attenuated in XY compared to XX animals of both gonadal sexes. Importantly, this difference arises only in the absence of circulating sex hormones following gonadectomy and confirms the role of sex hormones in the remyelination process reported earlier by our group. Because a genotype-mediated difference only arises following gonadectomy, the chromosomal contribution to myelination and remyelination is subtle yet significant. To explain this difference, we propose a possible asymmetry in expression of myelination-related genes in XX versus XY mice that needs to be investigated in future studies.

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Section: Introductionmentioning

confidence: 99%

Sex chromosome complement influences functional callosal myelination

Moore¹,

Patel²,

Hannsun³

et al. 2013

Neuroscience

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“…There is some evidence that other steroids such as progesterone and testosterone also display immunomodulatory effects presumably through their cognate receptors (Shuster, 2008); however, the effects of estrogen have been far more extensively described. Nevertheless, both neurological and pathological findings have supported the notion that estrogens are potent anti-inflammatory as well as neuroprotective agents with a potential to serve as novel therapeutics for the treatment of autoimmune demyelination.…”

Section: Introductionmentioning

confidence: 99%

Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis

Blasko¹,

Haskell²,

Leung³

et al. 2009

Journal of Neuroimmunology

164

139

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The beneficial effects of estrogens in multiple sclerosis are thought to be mediated exclusively by the classical nuclear estrogen receptors ERα and ERβ. However, recently many reports revealed that estrogens are able to mediate rapid signals through a G protein-coupled receptor (GPCR), known as GPR30. In the present study, we set out to explore whether effects mediated through this receptor were anti-inflammatory and could account for some of the beneficial effects of estrogen. We demonstrate that GPR30 is expressed in both human and mouse immune cells. Furthermore a GPR30-selective agonist, G-1, previously described by us, inhibits the production of lipopolysaccharide (LPS)-induced cytokines such as TNF-α and IL-6 in a dose-dependent manner in human primary macrophages and in a murine macrophage cell line. These effects are likely mediated solely through the estrogen-specific receptor GPR30 since the agonist G-1 displayed an IC 50 far greater than 10 μM on the classical nuclear estrogen receptors as well as a panel of 25 other GPCRs. Finally, we show that the agonist G-1 is able to reduce the severity of disease in both active and passive EAE models of multiple sclerosis in SJL mice and that this effect is concomitant with a G-1-mediated decrease in proinflammatory cytokines, including IFN-γ and IL-17, in immune cells harvested from these mice. The effect of G-1 appears indirect, as the GPR30 agonist did not directly influence IFN-γ or IL-17 production by purified T cells. These data indicate that G-1 may represent a novel therapeutic agent for the treatment of chronic autoimmune, inflammatory diseases.

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“…A variety of pregnancy-factors can be involved in this immune shift, including sex hormones [10]–[12], which appear to be involved in regulating the immune response [13]. Estrogens, indeed, are known to exert opposing, bimodal, dose-specific effect to immune response: low levels facilitate a cell-mediated pro-inflammatory immune response, whereas their relatively high levels, such as those achieved during pregnancy, promote anti-inflammatory Th2 responses.…”

Section: Introductionmentioning

confidence: 99%

Learning from Nature: Pregnancy Changes the Expression of Inflammation-Related Genes in Patients with Multiple Sclerosis

et al. 2010

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BackgroundPregnancy is associated with reduced activity of multiple sclerosis (MS). However, the biological mechanisms underlying this pregnancy-related decrease in disease activity are poorly understood.MethodologyWe conducted a genome-wide transcription analysis in peripheral blood mononuclear cells (PBMCs) from 12 women (7 MS patients and 5 healthy controls) followed during their pregnancy. Samples were obtained before, during (i.e. at the third, sixth, and ninth month of gestation) and after pregnancy. A validation of the expression profiles has been conducted by using the same samples and an independent group of 25 MS patients and 11 healthy controls. Finally, considering the total group of 32 MS patients, we compared expression profiles of patients relapsing during pregnancy (n = 6) with those of relapse-free patients (n = 26).Principal FindingsResults showed an altered expression of 347 transcripts in non-pregnant MS patients with respect to non-pregnant healthy controls. Complementary changes in expression, occurring during pregnancy, reverted the previous imbalance particularly for seven inflammation-related transcripts, i.e. SOCS2, TNFAIP3, NR4A2, CXCR4, POLR2J, FAM49B, and STAG3L1. Longitudinal analysis showed that the overall deregulation of gene expression reverted to “normal” already within the third month of gestation, while in the post-partum gene expressions rebounded to pre-pregnancy levels. Six (18.7%) of the 32 MS patients had a relapse during pregnancy, mostly in the first trimester. The latter showed delayed expression profiles when compared to relapse-free patients: in these patients expression imbalance was reverted later in the pregnancy, i.e. at sixth month.ConclusionsSpecific changes in expression during pregnancy were associated with a decrease in disease activity assessed by occurrence of relapses during pregnancy. Findings might help in understanding the pathogenesis of MS and may provide basis for the development of novel therapeutic strategies.

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Hormonal Influences in Multiple Sclerosis

Cited by 15 publications

References 215 publications

Sex chromosome complement influences functional callosal myelination

Sex chromosome complement influences functional callosal myelination

Beneficial role of the GPR30 agonist G-1 in an animal model of multiple sclerosis

Learning from Nature: Pregnancy Changes the Expression of Inflammation-Related Genes in Patients with Multiple Sclerosis

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