Ousman, Shalina S.Hoghooghi, Vahid2018-09-202018-09-202018-08-16Hoghooghi, V. (2018). Cystatin C and sex dimorphism in experimental autoimmune encephalomyelitis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/32966http://hdl.handle.net/1880/107803This dissertation characterizes the role of a lysosomal enzyme inhibitor, Cystatin C (CysC), in an animal model of multiple sclerosis (MS), called experimental allergic encephalomyelitis (EAE). MS is an autoimmune disease characterized by infiltration of myelin reactive immune cells into the central nervous system (CNS) that is more prevalent in genetically susceptible women compared to men. Alteration in the level of CysC in the CNS of MS patients is known, but its role has not been determined. Towards clarifying the role of CysC in EAE, I initially hypothesized that CysC would have a beneficial function in EAE due to its protective role in another autoimmune disease, collagen-induced arthritis. Unexpectedly, using C57BL/6 and CysC null (CysCKO) mice, I discovered that CysC plays a detrimental role in female but not male EAE mice. This sex dimorphism in the function of CysC could also be observed in immune cell infiltration and demyelination in EAE. Towards elucidating the cellular mechanism(s) underlying the sex difference driven by CysC in EAE, I discovered that the protease inhibitor promotes the activation of antigen presenting cells such as macrophages in females that subsequently mediates stimulation of CD4+ T cells. The T cell activation-promoting ability of CysC in female macrophages appears to be related to antigen presentation in macrophages since molecular mediators of antigen processing and loading (LC3II) and presentation (CD80, CD86, MHC II) were disrupted in female, but not male, macrophages that lacked CysC. Cumulatively, these observations indicate that CysC drives sex dimorphism in macrophages. Lastly, to understand why CysC would induce sex differences in macrophage function and thus EAE susceptibility, I investigated if sex hormones were involved. I found that CysC plays a detrimental role in EAE in the presence of estrogen. This dissertation thus provides novel evidence that CysC has a role in mediating sex dimorphism in EAE.engUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.NeuroscienceImmunologydoctoral thesis10.11575/PRISM/32966