Parent-of-Origin Sex Chromosome Effects on the Immune and Central Nervous System During Experimental Autoimmune Encephalomyelitis

Multiple sclerosis (MS) is an autoimmune demyelinating disease characterized by increased susceptibility in women. However, when men get the disease, they demonstrate more rapid disease progression, thus presenting a clinical enigma of the pathogenic events in MS susceptibility and progression. Of the sex-related factors that may contribute to MS susceptibility, much of the literature on the MS model, experimental autoimmune encephalitomyelits (EAE), has focused on the role of sex hormones in immune responses. While sex hormones have been demonstrated to affect autoimmune responses and neurodegeneration in EAE, it does not preclude sex chromosome effects. Indeed, previous work from our lab has demonstrated that the sex chromosome complement of immune cells affected autoimmune responses, with the XX sex chromosome complement, as compared to XY, leading to greater encephalitogenicity during auto-antigen stimulation. These results are consistent with human clinical observations of increased autoimmunity in women vs. men. This dissertation builds upon this finding by exploring the nature of sex chromosome effects in the female bias in autoimmunity through the use of transgenic sex chromosome mouse models that include the following genotypes: XX, XY-, XmY*x and XpY*x. Through a series of experiments, I demonstrate that parental imprinting of the X chromosome gene, forkhead box P3 (Foxp3), a master-regulator of T regulatory (Treg) cell development, results in increased FoxP3+ Tregs in XY- mice vs. XX mice.While sex chromosome effects have been identified in the immune system, it remained unclear if there were separate sex chromosome effects in the target organ, the CNS, response to an immune attack during EAE. This question is addressed in another portion of my dissertation. I created a bone marrow chimera model with mice bearing a common immune system, but varying sex chromosome complement in the CNS using the aforementioned transgenic sex chromosome mouse models, to examine the effects of sex chromosomes in the CNS during neurodegeneration. Through a series of experiments, I demonstrated that mice with CNS cells expressing XY sex chromosome complement, as compared to XX, led to greater neurodegeneration. Further, increased neurodegenerative response in the XY CNS was due to the maternal X allele. Together, these results demonstrated for the first time an affect of parental imprinting resulting in female bias on the autoimmune responses, and male bias in neurodegeneration during EAE. These findings may bear relevance to the clinical observations of female bias in susceptibility, but increased disability progression in men with MS