Sex Chromosome Complement Affects The CNS Neurodegenerative Response To Injury

Background: Women are more susceptible to multiple sclerosis and have more robust immune responses than men.  However, men with MS tend to dem­onstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack.  We have previously shown in a multiple sclerosis model, experimental autoimmune encephalomyelitis (EAE), that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic.  These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury.  

Objectives: The objective of this study is to determine if sex chromosomes may play a role in the CNS response to injury during EAE.

Methods: To test whether sex chromosomes may directly influence the CNS response to injury, we used SJL transgenic mice, in which the testis-determining factor Sry has been deleted from the Y chromosome (denoted Y^-).  Comparisons between XX and XY^- mice reveal effects of sex chromosomes not confounded by differences in types of gonadal hormones since both are female.  We then generated bone marrow chimeras of XX and XY^- gonadal female mice in which the sex chromosome complement of the reconstituted immune system was varied independently of that in the brain.  Thus, we were able to examine sex chromosome effects in the CNS during EAE without confounding effects of differences in sex chromosome complement in the immune system. 

Results:  We show that EAE mice with XY sex chromosome complement in the CNS, compared with XX, demonstrate greater clinical disease severity with more neuropathology in spinal cord and cerebellum.  Specifically, mice with XY CNS as compared to XX had lower myelin staining intensity and few numbers of axons in the spinal cord, and lower myelin staining intensity in the white matter and few numbers of Purkinje cells in the cerebellum.  Assessment of autoantigen specific peripheral immune responses in spleens as well as levels of CNS inflammation demonstrated no differences between bone marrow chimeras with XX vs. XY CNS and a common immune system.  

Conclusions: Our results suggest that sex chromosome effects on neurodegeneration in the CNS (XY>XX) may run counter to effects on immune responses (XX>XY).  These results may provide insight into why there is greater disease susceptibility in women but faster disability progression in men.