Brendan Cordeiro

Conference 2023 Live Talk

Talk title

Sex differences in the effect of obesity on adaptive immunity in a model of multiple sclerosis

Authors and Affiliations

Brendan Cordeiro1, Jeeyoon Jennifer Ahn6, Carmen Ucciferri6, Nuria Alvarez1, Cameron Whalen1, Daniel Winer2, Helena Lei3, Sue Tsai3, Danila Leontyev4, Natalie Stickle5, David Brooks5,6, Fei Linda Zhao6, Paulina Drohomyrecky6 and Shannon Dunn1,6

1. St. Michael’s Hospital, Keenan Research Institute, Unity Health Toronto, Ontario, Canada
2. Buck Institute for Research on Aging, California, USA
3. Toronto General Hospital Research Institute, Ontario, Canada
4. Canadian Blood Services, Ontario, Canada
5. Princess Margaret Cancer Centre, Ontario, Canada
6. University of Toronto, Department of Immunology, Ontario, Canada

Abstract

Background

Multiple Sclerosis (MS) is a chronic and incurable neurological disorder that affects more than 2.5 million people worldwide. What causes the initial autoimmune reaction in MS is unknown but both genetic and environmental factors are thought to be involved. Female physiology increases MS risk by more than 3-fold and is one of the largest risk factors for developing this disease. Interestingly, the ratio of men and women diagnosed with MS has been steadily, suggesting that environmental factors are interacting with female sex to increase MS risk. Epidemiological studies have identified that adolescent obesity is strongly associated with development of MS and that this association was significant only in females. Previous work utilizing the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), has shown that obesity in male mice promotes disease severity but no studies have been done utilizing female mice, the sex most vulnerable to this MS risk factor. Based on these observations, we put forward the central hypothesis that female sex and obesity interact to enhance CNS autoimmunity.

Methods

Obesity was induced in mice via the diet-induced obesity (DIO) model, where genetically susceptible mice are fed a high fat diet (HFD) enriched in saturated fat from lard (40-60% of kcal) ad libitum. We found that 4 weeks of HFD was sufficient to induce obesity in both sexes with minimal metabolic impairment. Active EAE was induced in control mice and in mice fed a HFD and assessed daily for disease severity. Flow cytometric analysis of splenic immune populations was done to assess the effects of DIO on T cell responses. CD4+ T cells were isolated from overweight healthy human females and males to determine if our findings were conserved in humans.

Results

Male and female mice fed a HFD showed an increase in EAE disease severity compared to controls, but this effect was more pronounced in female mice. We observed that this was a result of an enhanced CD4+ Interferon (IFN)-γ+ response that was selectively induced in female mice by DIO. In agreement with our mouse studies, CD4+ T cells isolated from overweight healthy human females, but not males, produced more IFN-γ compared to age matched controls. Further analysis revealed that this enhanced IFN-y response was due to an intrinsic enhancement of IFN-γ production and signaling in female CD4+ T cells.

Conclusions

These results highlight that an overweight state may interact with female sex to increase T cell IFN signaling.