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

of IFN gamma (IFN-γ) and T-cells differentiation; signal multiple HT susceptibility genes, including CTLA-4
transducer and activator of transcription 4, 58,61 which (chr2q22), PTPN22 (chr1p13), and VDR (chr12q13).
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is activated by IFN and regulates lymphocytic response Several lines of evidence highlight the possible roles of
to IL12 and T-cell differentiation; and oligoadenylate the X chromosome in HT. First, HT is female-biased in
synthetase 1, another IFN-regulated genes, known for prevalence. Second, X-monosomy (45, X0) in peripheral
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its involvement in apoptosis and frequent overexpression white blood cells – predominantly T and B lymphocytes
in autoimmune phenotype. Notably, similar to current – was found to be more frequent in females affected with
knowledge about biochemical signaling in SLE, most autoimmune thyroid disease compared with healthy
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of these genes are involved in molecular processes of females. Third, skewed XCI was found more common in
response to IFN. It is known that the primary biological HT subjects than healthy controls. 72,73
risk factor for SS is the female sex. SS is the most female-
biased autoimmune disorder, with a female-to-male sex 4. X-linked genes and mechanisms involved
ratio up to 20:1. Females carrying a 47, XXX karyotype in the pathogenesis of sex-biased ADs
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seem to harbor an increased risk of SS compared to typical, The mammalian X chromosome plays a crucial roles
46, XX females. Males affected carrying a complete in immune system functioning and is believed to
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or partial 47, XXY karyotype (Klinefelter’s syndrome) significantly influence sexual dimorphisms observed
harbor a similar risk of developing SS compared to typical not only in the risk but also in the expressivity of ADs.
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46, XX females. Altogether, these epidemiological data Several X-linked primary immunodeficiencies have been
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support a prominent role for the X chromosome dosage characterized. Representative examples are Wiskott-
on the risk of SS. Interestingly, rare structural X-linked Aldrich syndrome, caused by mutations in WAS ; X-linked
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aberrations involving a partial segment triplication within agammaglobulinemia, caused by mutations in BTK ; and
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the Xp11 region were identified in genetic analyses of over X-linked severe combined immunodeficiency. These
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2,000 women with SS. Although a larger patient sample conditions predominantly affect males. The impact of
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size is needed to identify additional cases, these genetic increased X chromosome dosage on the risk of ADs is
anomalies may pinpoint risk regions – including protein- notable, as observed in X-linked aneuploidies. 47, XXY
coding and non-coding RNAs – that are functionally males exhibit substantially higher AD risk compared to 46,
sensitive to X-dosage and involved in SS pathogenesis and XY males. Similarly, 47, XXX females may also face an
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pathophysiology. increased risk of ADs compared to 46, XX females. Data
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regarding Turner’s syndrome (45, X0) are mixed; some
3.3. HT reports suggest that 45, X0 females are at lower risk of
Similar to SLE and SS, HT (also known as chronic ADs, 18,77 while others reported autoimmune manifestations
lymphocytic thyroiditis) exhibits among the most in 45, X0 females and higher risk of autoimmune thyroiditis
significant female-biased incidence. HT is characterized by and inflammatory bowel disease. 78-80 As the copy number
auto-antibodies against the main thyroid antigens: Thyroid of X-linked genes could impact disease risk, immune-
peroxidase and thyroglobulin. These autoantibodies related genes escaping X-inactivation, which show partial
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attack the thyroid gland, with lymphocytes infiltrating the to complete biallelic X-linked expression, are potential
thyroid and causing inflammation and gradual destruction contributors to disease risk and expressivity, as well as
of thyroid tissue. HT often causes hypothyroidism, where phenotypic variability among females carries of X-linked
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the thyroid fails to produce sufficient levels of hormones. heterozygous conditions. 32,36
The exact nature of the molecular determinants of HT Several distinct X-linked mechanisms have been
etiology remains not completely understood. The disease proposed as determinant of ADs. Skewed XCI is one such
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predominantly affects women, with a higher incidence mechanism that may disrupt tolerance mechanisms. 16,81,82
in those aged 30 – 50. There is evidence on the genetic According to this hypothesis, it is crucial for antigen-
susceptibility of HT. Twin studies calculated that over 70% presenting cells to harbor balanced representation of
of the risk of developing thyroid autoantibodies can be both X-linked alleles. If subset of dendritic cells exhibit
attributed to genetics. Earlier analyses of the sibling risk pronounced skewing in XCI, their ability to identify and
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ratio confirmed that the development of HT has significant eliminate autoreactive T-cells may be compromised, as
genetic components. Later analyses of families revealed biased toward maternal or paternal self-antigens. As a
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that children and sibling of individuals affected with result, non-tolerized, autoreactive T-cells infiltrate and
autoimmune thyroid disease carried a 32-fold and 21-fold propagate into the hematopoietic system, triggering
higher risk of developing HT, respectively. Association autoimmune reactions. Higher XCI-skew has been
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studies and functional genomics screenings revealed observed in individuals affected with rheumatoid
Volume 4 Issue 2 (2025) 4 doi: 10.36922/gpd.8321