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REVIEW ARTICLE

Sex differences in autoimmune disorders: Inspecting the roles of the X chromosome

Matteo Capici1* ,  Antonino Zito2,3*
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1 Department of Biomedicine, Neuroscience and Advanced Diagnostics, School of Medicine and Surgery, University of Palermo, Palermo, Italy
2 Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy
3 Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
GPD, 8321 https://doi.org/10.36922/gpd.8321
Submitted: 31 December 2024 | Revised: 25 February 2025 | Accepted: 25 February 2025 | Published: 13 March 2025
© 2025 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Autoimmune disorders are complex, heterogeneous conditions that can severely impact an individual’s quality of life. These diseases are associated with a breakdown of central and peripheral processes controlling self-tolerance, causing the presence of circulating autoreactive immune cells that target the body’s own cells and tissues. Some data suggest that autoimmune diseases (ADs) are becoming increasingly prevalent in modern society. Possibly, both genetic and environmental factors contribute to the rise. ADs disproportionally affect females compared to males. Hormonal determinants, particularly sex-steroid hormones, have historically been proposed as key modulators of the differential susceptibility to ADs between the mammalian sexes. Emerging evidence has more recently generated significant focus on the X chromosome as a potential key player in ADs pathogenesis. The X chromosome, one of the largest chromosomes in the mammalian genome, exhibits a different pattern of inheritance between the sexes. In females, one X chromosome is typically silenced in somatic cells to balance the active X dosage between the sexes. The X-inactivation process is not fully efficient as a proportion of X-linked genes is capable to escape silencing and maintaining variable, biallelic expression degree within each cell. Notably, the X chromosome is rich in genes related to immune functions; variations in X chromosome dosage can alter the susceptibility of developing autoimmune traits. Both X-linked genes and X-linked mechanisms have been associated with ADs. In this review, we discuss the X chromosome’s crucial roles in ADs.

Graphical abstract
Keywords
Autoimmune diseases
Sex differences
X-chromosome inactivation
Skewed X-inactivation
Escape from X-inactivation
Systemic lupus erythematosus
Sjogren’s syndrome
Hashimoto’s thyroiditis
Funding
None.
Conflict of interest
The authors declare they have no competing interests.
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Gene & Protein in Disease, Electronic ISSN: 2811-003X Published by AccScience Publishing
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