Page 61 - GPD-4-2

Gene & Protein in Disease

REVIEW ARTICLE
Sex differences in autoimmune

disorders: Inspecting the roles of the X
chromosome

Matteo Capici * and Antonino Zito *
2,3
1
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

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
*Corresponding authors: proposed as key modulators of the differential susceptibility to ADs between the
Matteo Capici mammalian sexes. Emerging evidence has more recently generated significant
(matteo.capici@community.unipa.it) focus on the X chromosome as a potential key player in ADs pathogenesis. The X
Antonino Zito
(antonino.zito@unipa.it) chromosome, one of the largest chromosomes in the mammalian genome, exhibits
a different pattern of inheritance between the sexes. In females, one X chromosome
Citation: Capici M, Zito A. Sex is typically silenced in somatic cells to balance the active X dosage between the
differences in autoimmune
disorders: Inspecting the roles of the sexes. The X-inactivation process is not fully efficient as a proportion of X-linked
X chromosome. Gene Protein Dis. genes is capable to escape silencing and maintaining variable, biallelic expression
2025;4(2):8321. degree within each cell. Notably, the X chromosome is rich in genes related to
doi: 10.36922/gpd.8321
immune functions; variations in X chromosome dosage can alter the susceptibility of
Received: December 31, 2024 developing autoimmune traits. Both X-linked genes and X-linked mechanisms have
Revised: February 25, 2025
Accepted: February 25, 2025 been associated with ADs. In this review, we discuss the X chromosome’s crucial roles
Published online: March 13, 2025 in ADs.
Copyright: © 2025 Author(s).
This is an Open-Access article
distributed under the terms of the Keywords: Autoimmune diseases; Sex differences; X-chromosome inactivation; Skewed
Creative Commons Attribution X-inactivation; Escape from X-inactivation; Systemic lupus erythematosus; Sjogren’s
License, permitting distribution, syndrome; Hashimoto’s thyroiditis
and reproduction in any medium,
provided the original work is
properly cited.
Publisher’s Note: AccScience 1. Introduction
Publishing remains neutral with
regard to jurisdictional claims in
published maps and institutional Autoimmune diseases (ADs) are a diverse class of conditions arising from aberrant
affiliations. immune responses against individual’s own molecular and cellular constituents. ADs

Volume 4 Issue 2 (2025) 1 doi: 10.36922/gpd.8321