Sex Differences in the Blood Transcriptome Identify Robust Changes in Immune Cell Proportions with Aging and Influenza Infection
Erika Bongen,
Haley Lucian,
Avani Khatri,
Gabriela K. Fragiadakis,
Zachary B. Bjornson,
Garry P. Nolan,
Paul J. Utz,
Purvesh Khatri
Affiliations
Erika Bongen
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA, USA
Haley Lucian
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA
Avani Khatri
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA
Gabriela K. Fragiadakis
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
Zachary B. Bjornson
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
Garry P. Nolan
Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
Paul J. Utz
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author
Purvesh Khatri
Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA 94305, USA; Corresponding author
Summary: Sex differences in autoimmunity and infection suggest that a better understanding of molecular sex differences will improve the diagnosis and treatment of immune-related disease. We identified 144 differentially expressed genes, referred to as immune sex expression signature (iSEXS), between human males and females using an integrated multi-cohort analysis of blood transcriptome profiles from six discovery cohorts from five continents with 458 healthy individuals. We validated iSEXS in 11 additional cohorts of 524 peripheral blood samples. When we separated iSEXS into genes located on sex chromosomes (XY-iSEXS) or autosomes (autosomal-iSEXS), both modules distinguished males and females. iSEXS reflects sex differences in immune cell proportions, with female-associated genes showing higher expression by CD4+ T cells and male-associated genes showing higher expression by myeloid cells. Autosomal-iSEXS detected an increase in monocytes with age in females, reflected sex-differential immune cell dynamics during influenza infection, and predicted antibody response in males, but not females. : Bongen et al. identify a 144-gene immune sex expression signature (iSEXS) that is differentially expressed in the blood of healthy human males and females. Many of the autosomal-iSEXS genes are driven by sex differences in immune cell proportions and predict antibody responses to influenza infection in males, but not females. Keywords: multi-cohort analysis, meta-analysis, sex differences, transcriptome, immunology, immune system, influenza, CD4+ T cells, monocytes, aging
