Effects of Puberty and Obesity on Central Nervous System Autoimmunity in Experimental Autoimmune Encephalomyelitis
Multiple sclerosis (MS) is a chronic neuroinflammatory disease that is characterized by the formation of inflammatory demyelinating lesions in the central nervous system (CNS) white matter. One of the largest risk factors for developing MS is being female. The female preponderance of MS only manifests post-puberty implicating hormonal factors in this biology. Several other MS risk factors including obesity only impact MS risk when experienced post-puberty. The mechanisms of how puberty and obesity enhance MS risk are unknown. This thesis aimed to investigate how puberty in females (Chapter 2) and adolescent obesity (Chapter 3) increase autoimmune susceptibility in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE). First, EAE development was compared between age-matched SJL/J mice that differed only by pubertal status. It was observed that puberty in females, but not males, was associated with increased susceptibility to EAE. Additional studies performed in female mice revealed that myelin-specific T helper (Th) cell responses were more robust post-puberty as a result of more efficient antigen-presenting cell (APC) function. These findings suggest that the female adaptive immune system matures with puberty. In Chapter 3, we evaluated the effect of diet-induced obesity (DIO) on the development of EAE in adolescent female and male C57BL/6J mice. We observed that short-term (3-4 weeks) exposure to high-fat diet starting at 6 weeks of age resulted in modest weight gain in both sexes. Upon induction of EAE, mice on high-fat diet developed more severe EAE; this effect was particularly striking in female mice. Further studies performed in diseased mice revealed that DIO increased the number of myelin-specific and CD44hi Th cells in mice of both sexes but had the unique effect of enhancing Th1 responses in females. DIO also increased the potential of naïve CD4+ T cells from non-immunized mice to secrete IFN-γ in response to anti-CD3 and anti-CD28. This effect was more prominent in female CD4+ T cells and was associated with upregulation of IFN-γ-induced STAT1 signaling. Together, these studies contribute to the understanding of how puberty and adolescent obesity enhance CNS autoimmune susceptibility in females.
autoimmunity, diet-induced obesity, puberty
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