Grant: Pr. Gr.- PA: Sex/Gender in Health Res.- Understanding sex/gender mech./processes

The incidence of multiple sclerosis (MS) has been increasing over the past half-century, particularly in females, suggesting that changing environmental factors are interacting with female physiology to increase this disease. Obesity is one of these factors. For example, studies that examined population health data have found that obesity in late childhood doubles the risk of MS and that this association is stronger in females; however, the underlying mechanisms of why and how this occurs are unclear. By modelling the effect of diet-induced obesity in mice, we have discovered that fat gain associated with a high-fat diet enhances the development of a pro-inflammatory response called "T helper 1" or "Th1" selectively in females and that this is associated with a worsening of an MS-like disease in mice. Our studies further found that this T cell phenotype appears to be linked to greater levels of cytokines called type I interferons in the obese mice. We also found that the number of self-reactive T cells was greater in the obese compared to the control female mice; whether this relates to these higher levels of type I IFNs has not yet been investigated. We also do not yet understand the source of interferons, but we anticipate that it is coming from the adipose tissue, since the levels correlate with body weight gain. Here, we will investigate the mechanisms by which type I IFNs enhance the severity of MS-like disease in mice. We will also map the cell source and cause of the greater levels of type I IFNs in males and females under different nutritional states. The impact of this work is that we will learn more about how female physiology is connected to greater immunity and autoimmunity. As well, this work may find new ways to intervene to prevent MS.