All ETDs from UAB

Advisory Committee Chair

Chander Raman

Advisory Committee Members

Etty Benveniste

Suzanne M Michalek

John D Mountz

Hubert M Tse

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Lithium, a glycogen synthase kinase 3 (GSK3) inhibitor, ameliorates experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS) in different mouse models. However, the mechanism of lithium's attenuation of EAE and the role of GSK3 in these processes are currently unknown. IFN-g producing Th1 cells and IL-17-producing Th17 cells are both effector cells in MS and in EAE models. However, relapsing remitting MS patients segregate into Th1 or Th17 serum cytokine signatures and each is differentially responsive to IFN-ß therapy, a first line therapy for MS. Studies in this dissertation revealed a differential effect of lithium on Th1 and Th17 diseases: lithium is protective against Th1 but not Th17 EAE. We identified a novel mechanism in the pathogenesis of EAE in which inhibition of GSK3 is beneficial in suppressing disease via modulation of the IFNg-STAT1 signaling pathways. On the other hand, lithium pre-treatment is protective against induction of EAE disease. In this dissertation, we evaluated the effect of lithium on processes involved in the initiation of EAE. We found that lithium treatment had no effect on antigen processing and presentation or subsequent T cell proliferation. Additionally, we examined the effect of lithium on limiting the inflammatory response through apoptosis and found no effect on apoptosis of antigen-specific CD4+ T cells. We also evaluated if the source of lithium's protection against EAE induction was through modulation of chemokine expression. Here we report decreased expression of IFN-g induced chemokines (CCL2, CCL5, CXCL9) in CNS tissue from lithium-treated EAE animals, consistent with our finding that GSK3 mediates IFN-g-induced STAT1 activation. Additionally, these findings are consistent with the reversibility of lithium's protection upon withdrawal; indeed, lithium's modulation of IFN-g signaling is likely important for both preventing the initiation of EAE, as well as attenuating the propagation of the disease. Overall, we have evaluated the effect of lithium therapy on several critical pathways involved in the pathogenesis of EAE. We have described the role of GSK3 in modulating IFN-g-induced STAT1 activation, an important pathway in EAE and, likely, other IFN-g-mediated inflammatory diseases.



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