title: Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza 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.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305-5323.
authors.forename: David
authors.initials: D
authors.lastname: Furman
authors.forename: Boris P
authors.initials: BP
authors.lastname: Hejblum
authors.forename: Noah
authors.initials: N
authors.lastname: Simon
authors.forename: Vladimir
authors.initials: V
authors.lastname: Jojic
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Dekker
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Thiébaut
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Tibshirani
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
mesh_terms: D000367:Age Factors; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001185:Artificial Intelligence; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D007252:Influenza Vaccines / Q000276:immunology*; D007963:Leukocytes, Mononuclear; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis; D009500:Neutralization Tests; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012727:Sex Characteristics; D049490:Systems Biology; D013739:Testosterone / Q000097:blood / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D016207:Cytokines; D007252:Influenza Vaccines; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013739:Testosterone
keywords: aging; gender; immuno-endocrine; immunosenescence; sexual dimorphism