Sex Differences in MS Are Genetic, Not Just Hormonal
In contrast to their influence on immune system reactivity, female chromosomes confer protection to the central nervous system
When it comes to sex differences, multiple sclerosis presents a paradox: Although women are more likely to get MS, men who do get the disease experience a more precipitous decline into disability. New work from Rhonda Voskuhl, M.D., and colleagues at the University of California, Los Angeles, now shows that genes on the sex chromosomes—not just the cascade of hormones they set into motion—determine gender susceptibility to disease. Moreover, the genetic influence appears to be tissue-specific. The work was published online February 3 in the Proceedings of the National Academy of Sciences (Du et al., 2014).
In order to separate the effects of sex differences on the immune system from those on the central nervous system (CNS), the researchers used a line of transgenic mice in which the male sex-determining Sry region of the Y chromosome had been removed (XY–). Autosomal replacement of Sry with a transgene allowed XY– mice to father pups. All XX and XY– mice were hormonally female, removing the gonadal influence from the equation.
Voskuhl’s group had previously shown that when wild-type mice received sensitized lymph node cells—a way of inducing experimental autoimmune encephalomyelitis (EAE), a model of MS—cells from XX mice caused a more severe sickness than cells derived from XY– mice, suggesting that genes on the X chromosome made the immune cells more pernicious (Smith-Bouvier et al., 2008).
For the current study, in order to further tease apart the influence of sex genes on the immune system versus on the CNS, the researchers used four combinations of mice: those with XX CNS and immune system, XY– CNS and immune system, XX CNS but XY– immune system, and XY– CNS with XX immune system. Late in EAE progression, mice that had genetically XY– CNS complement fared worse on clinical measures of disease compared to XX CNS mice. Anatomical changes reflected the behavioral outcomes: XY– CNS mice also had more demyelination and axon loss in the spinal cord and cerebellum and more synaptic loss in the cortex than did XX CNS mice.
Together, the findings suggest that X-linked genes conferred some protection in the CNS—the opposite of their influence on the immune system.
The authors next homed in on an X-linked gene known to participate in neurodegenerative processes: toll-like receptor 7 (Tlr7). Mice with XY– CNS had more Tlr7-expressing neurons—but not microglia—than their XX CNS counterparts, hinting that the receptor might contribute to the greater CNS susceptibility. Interestingly, the researchers found no sex-linked influence of the immune system on EAE severity when CNS complement genotype was the same (either XX or XY–).
More work will be required to sort out how sex-linked genes sway the brain and immune system toward resilience or decline, but the new report confirms that the question is worth investigating.
Key open questions
- Why did XY– mice express more X-linked Tlr7 than XX mice, and how does Tlr7 contribute to neuronal degeneration in EAE?
- What other genes on the X (or Y) chromosomes might confer protection or susceptibility in the brain and immune system?
The authors reported no disclosures. The research was supported by funds from the National Institutes of Health (NIH), the National MS Society, the Conrad M. Hilton Foundation, the Jack H. Skirball Foundation and the Sherak Family Foundation.