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Decoding sex differences in human immunity through systems immunology

Escrivà-Font, Joan LU orcid ; Cao, Tianze LU orcid and Consiglio, Camila Rosat LU (2025) In Oxford Open Immunology 6(1).
Abstract

Immune function varies widely across humans. Biological sex is a key factor underlying human immune variability, with men presenting with more severe infections and increased cancer rates, while women exhibit higher vaccine responses and prevalence of autoimmunity. Intrinsic biological sex differences arise from varying contributions of chromosomal sex, and sex hormone sensing and downstream signaling to different cell types. This complex regulation presents a unique opportunity for the exploration of human immune sex differences using systems-level methods of investigation. Here we analyze the current literature and the applications of systems immunology in elucidating the immune sex differences in humans. We examine mechanisms of... (More)

Immune function varies widely across humans. Biological sex is a key factor underlying human immune variability, with men presenting with more severe infections and increased cancer rates, while women exhibit higher vaccine responses and prevalence of autoimmunity. Intrinsic biological sex differences arise from varying contributions of chromosomal sex, and sex hormone sensing and downstream signaling to different cell types. This complex regulation presents a unique opportunity for the exploration of human immune sex differences using systems-level methods of investigation. Here we analyze the current literature and the applications of systems immunology in elucidating the immune sex differences in humans. We examine mechanisms of biological sex modulation of human immunity via sex chromosomes, and particularly emphasize the role of sex hormones. We then focus on how systems immunology has been advancing our understanding of how sex impacts the healthy immune system at steady state, ranging from cell composition, transcriptomics, epigenomics, metabolomics, spatial and cell-cell interactions, to plasma proteomics. We also examine systems-level applications to investigating sex differences upon immune perturbations and give an overview of key future directions for the field. Systems immunology provides a powerful framework to decode biological sex-regulated pathways in immunity, paving the way for more precise, sex-informed therapeutic interventions to address sex differences in immune-related conditions.

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Please use this url to cite or link to this publication:
author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oxford Open Immunology
volume
6
issue
1
article number
iqaf006
publisher
Oxford University Press
external identifiers
  • scopus:105011485245
  • pmid:40692743
ISSN
2633-6960
DOI
10.1093/oxfimm/iqaf006
language
English
LU publication?
yes
additional info
© The Author(s) 2025. Published by Oxford University Press.
id
63b8295a-4e34-455d-a2d3-fa16a42067f7
date added to LUP
2025-09-17 11:17:01
date last changed
2025-10-16 07:47:03
@article{63b8295a-4e34-455d-a2d3-fa16a42067f7,
  abstract     = {{<p>Immune function varies widely across humans. Biological sex is a key factor underlying human immune variability, with men presenting with more severe infections and increased cancer rates, while women exhibit higher vaccine responses and prevalence of autoimmunity. Intrinsic biological sex differences arise from varying contributions of chromosomal sex, and sex hormone sensing and downstream signaling to different cell types. This complex regulation presents a unique opportunity for the exploration of human immune sex differences using systems-level methods of investigation. Here we analyze the current literature and the applications of systems immunology in elucidating the immune sex differences in humans. We examine mechanisms of biological sex modulation of human immunity via sex chromosomes, and particularly emphasize the role of sex hormones. We then focus on how systems immunology has been advancing our understanding of how sex impacts the healthy immune system at steady state, ranging from cell composition, transcriptomics, epigenomics, metabolomics, spatial and cell-cell interactions, to plasma proteomics. We also examine systems-level applications to investigating sex differences upon immune perturbations and give an overview of key future directions for the field. Systems immunology provides a powerful framework to decode biological sex-regulated pathways in immunity, paving the way for more precise, sex-informed therapeutic interventions to address sex differences in immune-related conditions.</p>}},
  author       = {{Escrivà-Font, Joan and Cao, Tianze and Consiglio, Camila Rosat}},
  issn         = {{2633-6960}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{1}},
  publisher    = {{Oxford University Press}},
  series       = {{Oxford Open Immunology}},
  title        = {{Decoding sex differences in human immunity through systems immunology}},
  url          = {{http://dx.doi.org/10.1093/oxfimm/iqaf006}},
  doi          = {{10.1093/oxfimm/iqaf006}},
  volume       = {{6}},
  year         = {{2025}},
}