Sex chromosome contributions to sex differences in multiple sclerosis susceptibility and progression

Voskuhl, Rhonda R.; Sawalha, Amr H.; Itoh, Yuichiro

doi:10.1177/1352458517737394

Cited by 57 publications

(48 citation statements)

References 75 publications

(85 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our findings, combining RNA sequencing analysis of ON astrocytes in females, followed by investigation of lead targets by immunohistochemistry in ON and retina of both females and males, reveal an interesting difference in astrocyte reactivity in female versus male optic nerve. This sexual dimorphism may be due to differences in sex hormones or sex chromosomes 54,55 , either of which could modulate astrocyte reactivity in optic nerve in EAE. The fact that we did not observe this sex difference in spinal cord, makes the optic nerve unique and further underscores the heterogeneity of astrocytes across CNS regions 1,49 .…”

Section: Discussionmentioning

confidence: 99%

The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression

Tassoni

Farkhondeh

Itoh

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a neuroinflammatory multifocal disorder. Optic neuritis is common in MS and leads to visual disability. No current treatments repair this damage. Discerning gene expression changes within specific cell types in optic nerve (ON) may suggest new treatment targets for visual disability in MS. Astrocytes are pivotal regulators of neuroinflammation, playing either detrimental or beneficial roles. Here, we used RiboTag technology to characterize the astrocyte-specific transcriptome in ON in the experimental autoimmune encephalomyelitis (EAE) model of MS. RNA sequencing analysis showed the Complement Cascade and Cholesterol Biosynthesis Pathways as the most enriched and de-enriched pathways, respectively, in ON astrocytes in EAE. Expression of complement component 3 (C3) was confirmed to be increased in ON astrocytes at the protein level during EAE. A bigger increase in C3 expressing ON astrocytes was found in EAE females versus healthy females, as compared to that in EAE males versus healthy males. Also, there was worse retinal ganglion cell (RGC) and axonal loss in EAE females. Regression analyses showed a negative correlation between C3 expressing astrocytes and RGC density. This cell-specific and sex-specific investigation of the optic nerve provides targets for the development of therapeutic strategies tailored for optic neuritis in MS.

show abstract

Section: Discussionmentioning

confidence: 99%

The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression

Tassoni

Farkhondeh

Itoh

et al. 2019

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, direct effects of sex chromosomes and indirect effects of sex chromosomes (mediated by sex hormones) on the immune system and the neurodegeneration phenomena observed in MS should also be considered. 128 Development of different mouse core genotypes backcrossed onto the SJL background, 129 has permitted the separation of effects of sex chromosomes from effects of sex hormones. Using these models, it has been possible to demonstrate that sex chromosomes have a direct effect in the induction of immune responses in adoptive EAE, which is unlikely to be mediated by different effects of different sex hormones.…”

Section: Prolactinmentioning

confidence: 99%

Impact of sex hormones on immune function and multiple sclerosis development

2018

View full text Add to dashboard Cite

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting young people and leading to demyelination and neurodegeneration. The disease is clearly more common in women, in whom incidence has been rising. Gender differences include: earlier disease onset and more frequent relapses in women; and faster progression and worse outcomes in men. Hormone-related physiological conditions in women such as puberty, pregnancy, puerperium, and menopause also exert significant influence both on disease prevalence as well as on outcomes. Hormonal and/or genetic factors are therefore believed to be involved in regulating the course of disease. In this review, we discuss clinical evidence for the impact of sex hormones (estrogens, progesterone, prolactin, and testosterone) on MS and attempt to elucidate the hormonal and immunological mechanisms potentially underlying these changes. We also review current knowledge on the relationship between sex hormones and resident CNS cells and provide new insights in the context of MS. Understanding these molecular mechanisms may contribute to the development of new and safer treatments for both men and women.

show abstract

“…One such transcript is KDM6a where the animals deficient for this gene were found resistant for the development of EAE [61]. Other potential candidates include Forkhead box P3 (FoxP3) and Toll like receptor (TLR) 7 [62]. Likewise, epigenetic modifications (DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs) at major histocompatibility complex (MHC) loci may influence sex differences in MS [51,63] ( Fig.…”

Section: Factors That Influence the Development Of Aidsmentioning

confidence: 99%

Mechanisms of sex hormones in autoimmunity: focus on EAE

Lasrado

Jia

Massilamany³

et al. 2020

Biol Sex Differ

View full text Add to dashboard Cite

Sex-related differences in the occurrence of autoimmune diseases is well documented, with females showing a greater propensity to develop these diseases than their male counterparts. Sex hormones, namely dihydrotestosterone and estrogens, have been shown to ameliorate the severity of inflammatory diseases. Immunologically, the beneficial effects of sex hormones have been ascribed to the suppression of effector lymphocyte responses accompanied by immune deviation from pro-inflammatory to anti-inflammatory cytokine production. In this review, we present our view of the mechanisms of sex hormones that contribute to their ability to suppress autoimmune responses with an emphasis on the pathogenesis of experimental autoimmune encephalomyelitis.

show abstract

Sex chromosome contributions to sex differences in multiple sclerosis susceptibility and progression

Abstract: Mapping the transcriptome and methylome in T lymphocytes and neurons in females versus males could reveal mechanisms underlying sex differences in autoimmunity and neurodegeneration.

Cited by 57 publications

References 75 publications

The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression

The astrocyte transcriptome in EAE optic neuritis shows complement activation and reveals a sex difference in astrocytic C3 expression

Impact of sex hormones on immune function and multiple sclerosis development

Mechanisms of sex hormones in autoimmunity: focus on EAE

Contact Info

Product

Resources

About