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The conneXion between sex and immune responses

Nature Reviews Immunology (2024)Cite this article

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Abstract

There are notable sex-based differences in immune responses to pathogens and self-antigens, with female individuals exhibiting increased susceptibility to various autoimmune diseases, and male individuals displaying preferential susceptibility to some viral, bacterial, parasitic and fungal infections. Although sex hormones clearly contribute to sex differences in immune cell composition and function, the presence of two X chromosomes in female individuals suggests that differential gene expression of numerous X chromosome-linked immune-related genes may also influence sex-biased innate and adaptive immune cell function in health and disease. Here, we review the sex differences in immune system composition and function, examining how hormones and genetics influence the immune system. We focus on the genetic and epigenetic contributions responsible for altered X chromosome-linked gene expression, and how this impacts sex-biased immune responses in the context of pathogen infection and systemic autoimmunity.

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Fig. 1: Sex differences with pathogen infections and autoimmune disease.
Fig. 2: Impairments in dynamic XCI maintenance result in aberrant overexpression of X-linked genes in female-biased autoimmune diseases.
Fig. 3: Number of X chromosomes and risk for autoimmune disease.

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Acknowledgements

The authors thank L. King and members of the Anguera laboratory for their input and feedback on the manuscript and figures. This work was supported by grants from the US National Institutes of Health (R01-AI134834 to M.C.A., T32 DK-07780 to K.S.F. and T32-AR076951-01 to N.J.), the Lupus Research Alliance TIL grant (to M.C.A.); the Rheumatology Research Foundation Future Physician Scientist Award (to C.D.L.), the Rheumatology Research Foundation Scientist Development Award (to N.J.), the Scleroderma Research Foundation Postdoctoral Award (to N.J.), the Penn Colton Center for Autoimmunity and the Institute for Immunology and Immune Health (to M.C.A. and N.J.), the Philadelphia Tri-State Chapter Goldie Simon Preceptorship Award (to C.D.L. and N.E.T.), the Lupus Foundation of America, Philadelphia Tri-State Chapter Gina M. Finzi Memorial Student Summer Awards (to C.D.L. and N.E.T.), and the H. Ralph Schumacher Rheumatology Research Fund (to N.J.).

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  1. Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Katherine S. Forsyth, Nikhil Jiwrajka, Claudia D. Lovell, Natalie E. Toothacre & Montserrat C. Anguera

  2. Division of Rheumatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Nikhil Jiwrajka

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Forsyth, K.S., Jiwrajka, N., Lovell, C.D. et al. The conneXion between sex and immune responses. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-00996-9

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