Tweet
Published online before print December 23, 2013, doi: 10.1073/pnas.1321060111
PNAS December 23, 2013
Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination
David Furmana,1,2,3,
Boris P. Hejblumb,1,
Noah Simonc,
Vladimir Jojicd,
Cornelia L. Dekkere,
Rodolphe Thiébautb,
Robert J. Tibshiranic,f, and
Mark M. Davisa,g,h,3
aDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5323;
bISPED-Epidemiologie-Biostatistique and Institut National de la Santé et de la Recherche Médicale (INSERM), Centre INSERM U897, University of Bordeaux, and INRIA–Statistics in System Biology and Translational Medicine Team, F-33000 Bordeaux, France;
cDepartment of Statistics, Stanford University, Stanford, CA 94305-4065;
dDepartment of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3175;
eDepartment of Pediatrics, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305-5208;
fDepartment of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305-5405;
gInstitute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305-5124; and
hHoward Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5323
Contributed by Mark M. Davis, November 21, 2013 (sent for review September 23, 2013)
Significance
There are marked differences between the sexes in their immune response to infections and vaccination, with females often having significantly higher responses. However, the mechanisms underlying these differences are largely not understood. Using a systems immunology approach, we have identified a cluster of genes involved in lipid metabolism and likely modulated by testosterone that correlates with the higher antibody-neutralizing response to influenza vaccination observed in females. Moreover, males with the highest testosterone levels and expression of related gene signatures exhibited the lowest antibody responses to influenza vaccination. This study generates a number of hypotheses on the sex differences observed in the human immune system and their relationship to mechanisms involved in the antibody response to vaccination.
Abstract
Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.
PNAS December 23, 2013
Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination
David Furmana,1,2,3,
Boris P. Hejblumb,1,
Noah Simonc,
Vladimir Jojicd,
Cornelia L. Dekkere,
Rodolphe Thiébautb,
Robert J. Tibshiranic,f, and
Mark M. Davisa,g,h,3
aDepartment of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5323;
bISPED-Epidemiologie-Biostatistique and Institut National de la Santé et de la Recherche Médicale (INSERM), Centre INSERM U897, University of Bordeaux, and INRIA–Statistics in System Biology and Translational Medicine Team, F-33000 Bordeaux, France;
cDepartment of Statistics, Stanford University, Stanford, CA 94305-4065;
dDepartment of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3175;
eDepartment of Pediatrics, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305-5208;
fDepartment of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305-5405;
gInstitute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305-5124; and
hHoward Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305-5323
Contributed by Mark M. Davis, November 21, 2013 (sent for review September 23, 2013)
Significance
There are marked differences between the sexes in their immune response to infections and vaccination, with females often having significantly higher responses. However, the mechanisms underlying these differences are largely not understood. Using a systems immunology approach, we have identified a cluster of genes involved in lipid metabolism and likely modulated by testosterone that correlates with the higher antibody-neutralizing response to influenza vaccination observed in females. Moreover, males with the highest testosterone levels and expression of related gene signatures exhibited the lowest antibody responses to influenza vaccination. This study generates a number of hypotheses on the sex differences observed in the human immune system and their relationship to mechanisms involved in the antibody response to vaccination.
Abstract
Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.
