IMMUNE RESPONSE STRONGER IN WOMEN

Androgens and genes involved in lipid metabolism may drive the differences in immune responses between men and women, according to a systems analysis

David Furman, PhD, from Stanford University in California, and colleagues measured the responses to diverse in vitro stimuli in peripheral blood samples from 53 women and 34 men.

"Males experience a greater severity and prevalence of bacterial, viral, fungal, and parasitic infections than females, who also exhibit a more robust response to antigenic challenges such as infection and vaccination," the authors write. "This stronger immune response in females could also explain why they more frequently develop immune-mediated pathologies during influenza infection, such as an overproduction of cytokines (cytokine storm) that contribute to an increase in capillary permeability and lung failure."

The researchers analyzed the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine and other immune system components. They also measured gene expression and reduced the data to 109 gene modules by cluster analysis. In this way, they identified proinflammatory markers that are differentially expressed in women as opposed to men.

"In this study we have used a systems approach to the analysis of sex differences in the immune system of humans. These data reinforce and extend previous reports, and point toward a mechanistic hypothesis that may drive sex disparities observed in responses to vaccination," the authors note.

Previous studies have identified sex-specific differences in the immune response. Women, for example, have on average 1.7 times the frequency of self-specific T cells as men.

Results from the current study indicate that natural variations in circulating free testosterone could drive differences in response to influenza vaccines. The investigators also identified differences in expression of several genes involved in lipid metabolism including LTA4H, a member of the epoxide hydrolase family. They also observed an association with LTB4, a lipid mediator that has both anti-inflammatory and proinflammatory activities.

The authors were unable to identify genes on the Y chromosome that affect the response to vaccination.

"In conclusion, our results are consistent with a large body of work in animals showing that testosterone is immunosuppressive in vivo and extend this to humans responding to a seasonal influenza vaccine and exhibiting typical variations in testosterone levels. We suggest that testosterone acts directly on immune cells by repressing transcription factors (such as FOS, JUN, and others) implicated in immune activation; these transcription factors would in turn repress the expression of genes involved in lipid metabolism with immunosuppressive activities, creating a negative feedback loop," the authors write.

They propose that testosterone acts as a homeostatic mechanism to turn off the immune response.

The authors have disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online December 23, 2013. Full text