Page 63 - GPD-4-2

Gene & Protein in Disease X chromosome in sex-biased autoimmunity

However, skewed (i.e., asymmetric) representation of a Table 1. Female prevalence for a subset of systemic and
parental, active X chromosome is commonly seen among organ‑specific autoimmune diseases
females, particularly in the aging population. 25-27 Both Female: Category References
genetic and non-genetic factors can contribute to skewed Male ratio
XCI. 25,28 At present, the exact identity of these factors is not Systemic conditions
known. Skewed XCI impacts the somatic XCI mosaicism
across cells and tissues. When restricted to certain immune Sjögren’s syndrome 20:1 Systemic 63
cell populations, skewed XCI could potentially modulate Systemic lupus erythematosus 9:1 Systemic 9
differences in X-linked gene expression between cells, Takayasu’s arteritis 9:1 Vasculitis 144
and consequently, impact the functions of the immune Systemic sclerosis 3:1 Systemic 145
system. Skewed XCI also occurs in the presence of Giant cell arteritis 3:1 Vasculitis 144
X-linked mutations, as in the case of asymptomatic female Rheumatoid arthritis 3:1 Systemic 146,147
carriers of Wiskott-Aldrich syndrome where the wild-type Organ-targeted conditions
allele is preferentially expressed in hematopoietic cells.
29
Crucially, the inactive X chromosome is not fully silent. Hashimoto’s thyroiditis 4 – 10:1 Thyroid 10
In humans, more than 20% of X-linked genes “escape” Grave’s disease 4:1 Thyroid 148
XCI and exhibit partial-to-complete expression from both Multiple sclerosis 3:1 Neurological 149
parental X chromosomes in a female somatic cell. 30-34 For
genes regulating immune system functions, escape from Among the upregulated genes, there are genes normally
XCI might increase their functional dosage and underlie subject to XCI, such as FOXP3 and IL2RG, but also known
sex differences in immune phenotypes. 33,35,36 As discussed escapees such as KDM5C and JPX. As discussed later
41
below, X-linked genes escaping XCI have been associated in this review, multiple other X-linked loci have been
with ADs. significantly linked to SLE pathogenesis and susceptibility,
3. Sex-biased ADs risk: A female-specific such as Toll-like receptor 7 (TLR7), CXorf21, TMEM187,
disadvantage and IRAK1, which all escape XCI. By escaping XCI, these
genes may exhibit partial to complete biallelic X-linked
Epidemiological and clinical data indicate that the female expression in female’s immune cells, contributing to gender
sex is at significantly higher risk for ADs compared to the differences in risk of ADs. 32,33,35
male sex (Table 1). In general, up to 80% of individuals with
a clinical diagnosis of an ADs are women. In discussing 3.2. Sjogren’s syndrome (SS)
the involvement of X-linked genes in ADs, we will focus SS is a systemic, chronic ADs which primarily affects the
on three prominent, sex-biased ADs: Systemic lupus lacrimal and salivary exocrine glands. Compared to other
erythematosus, Sjögren’s syndrome, and HT, all of which ADs, SS is more frequently associated with multiple types
show a prevalence reaching 80% in female patients. of lymphomas. 43,44 As for other ADs, age is a risk factor,
with most SS patients being at least 40 years old. There is
3.1. SLE
no approved therapy to cure SS. The determinants of SS
SLE is an autoimmune, systemic disease. Up to 90% remain under active investigation. While the presence of
of diagnosed patients are female. The female sex and a concurrent ADs, such as SLE or rheumatoid arthritis,
9
karyotypes with extra X chromosomes are at higher risk appears to boost the risk of developing SS, genetic
of SLE. SLE is a highly heterogenous disease. Clinical predisposition to SS is supported by cases of families
manifestations may range from mild mucocutaneous with multiple affected members. 45-51 Genome-wide
expressions to inflammatory involvements of the central association analyses for primary SS uncovered consistent
nervous system as well as multiple other organs. The signal within HLA genes, particularly at MHC Class II
exact etiology of SLE remains not well understood. At locus HLA-DRB1 in the Caucasian population. 52,53 Larger
molecular level, anti-nuclear autoantibodies and Type I studies, also including multiple ethnicities, provided
interferon (IFN) activity are detected. Multiple anomalies more detailed genetic associations at HLA Class II alleles
of B- and T-cell activity have been characterized in SLE. 37-40 DRB1 × 03:01, but also HLA-DQA1 and HLA-DQB1. 54-57
T-cells exhibit aberrant maintenance of XCI in individuals Beyond MHC genes, other genes associated or potentially
affected with SLE as well as in NZB/W F1 XX mice, which associated with SS have been reported, including IFN
develop a systemic, ADs highly similar to SLE. Up to a regulatory factor 5 (IRF5), 58,59 a transcription factor
41
hundred X-linked genes are overexpressed in T-cells from activating IFNA/B regulated also by TLR7-9; interleukin
SLE patient, 41,42 presumably resulting from X-reactivation. 12A (IL12A), a cytokine required for T-cell induction
60

Volume 4 Issue 2 (2025) 3 doi: 10.36922/gpd.8321