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

in the regulation of TLR7 and TLR8 signaling pathways. have reported IRAK1 as possibly subject to XCI. 33,119
CXorf21 roles in SLE have been recently investigated However, IRAK1 gene and protein expression levels in
in detail. Large genome-wide association analyses umbilical cord blood samples were found to be higher
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identified the Xp21.2 locus (rs887368) associated with SLE in females compared to males. Furthermore, IRAK1
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in Europeans. The polymorphism is most significantly expressed biallelically in memory B cells and plasmablast
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associated with the disease maps in the third exon of cells, suggesting the occurrence of more complex
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CXorf21. CXorf21 was found to be upregulated in SLE mechanisms and involvement in sex-biased phenotypes.
patients exhibiting disease progression compared to those CXCR3 (C-X-C motif chemokine receptor 3) is a
with a more stable infection. Functional characterization chemokine receptor that binds IFN-inducible ligand
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indicated that (i) CXorf21 expression levels are regulated chemokine and is activated by distinct IFN-inducible ligand
by IFN and that response to IFN is higher in females chemokines, including CXCL9, CXCL10 and CXCL11,
than males; (ii) CXORF21 protein colocalizes with TLR7 all of which respond to IFN-γ. These chemokines are
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protein, which is also implicated in SLE pathogenesis. upregulated in proinflammation and recruit immune
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Expression of CXorf21 is influenced by TLR7, and CXorf21 cells at inflammatory tissue sites. CXCR3 is primarily
disruptions impact IFN synthesis regulated by TLR7. 110,111 expressed CD4+ and CD8+ T cells and plays crucial roles
As CXorf21 closely interacts with TLR7, it is also believed in the regulation of Th cells response. 122,123 In SS, and
to be an SS susceptibility gene. CXorf21 escapes XCI and likely in other ADs, CXCR3 may promote inflammation
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is more highly expressed, at both RNA and protein levels, in and exacerbate disease symptoms and manifestation.
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female immune cells compared to male immune cells. 107,110 In SS patients, which may also exhibit dry eye-syndrome,
CXorf21 escape may also lead to greater protein levels in the expression levels of CXCR3 and its ligands CXCL9,
female SLE cells compared to healthy controls. These CXCL10, and CXCL11 are increased in ocular regions.
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data support a role for XCI escape in SLE pathogenesis. Another study reported that CXCR3 and its ligands may
However, further studies are needed to assess the extent be highly expressed in lacrimal and salivary glands of SS
to which altered, immune cell type-specific XCI-skew also patients. 126,127 A recent study assessed the expression of
contributes modulating CXorf21 expression levels. chemokine receptors and ligands in CCR9+ Th cells in
IRAK1 (Interleukin-1 receptor-associated kinase), primary SS patients and healthy controls. It was found
encodes for a serine/threonine kinase involved in innate that circulating CCR9+ Th cells exhibited higher CXCR3
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immune response through TLR signaling pathways. On levels compared to CCR9- Th cells. Patients affected with
TLR activation, IRAK1 is recruited to the receptor-signaling primary SS also had lower levels of circulating memory
complex. Once activated, IRAK1 may phosphorylate CCR9+ CXCR3+ Th cells compared to healthy controls,
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TRAF-6, with subsequent activation of nuclear factor kappa suggesting T cell subset alteration in SS associated with
B (NF-κB) and other pathways and expression of IL-1/6/12 cell migration upon inflammation and chemokine ligands
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cytokines. Previous studies reported multiple genetic overexpression. CXCR3 and ligands have also been
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polymorphisms in IRAK1 associated with both adult- and implicated in SLE pathogenesis and lupus nephritis.
childhood-onset SLE in distinct ethnic groups. Another CXCR3+ T cells are abundant in kidneys and urine of
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study, including nearly 16,000 case–control subjects, SLE patients with acute nephritis, offering potential as
identified six X-linked genetic polymorphisms mapped biomarkers and therapeutic targets. 130
in the region spanning TMEM187-IRAK1-MECP2 as to CD40L (CD40 ligand; also known as CD154) encodes
be significantly associated with SLE. The most significant for the ligand of CD40. It is a member of the tumor necrosis
signal was found at rs1059702, whose risk allele induces family. The CD40/CD40L pathway has been implicated in
amino acid change in IRAK1. The association of IRAK1 SS as crucially involved in both innate and humoral immune
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with SLE was supported by other, similar analyses. responses. 131,132 It is a protein predominantly expressed on
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Interestingly, in a mouse model of SLE, IRAK1 deficiency the surface of T cells and can bind CD40 on the surface
was able to restore normal phenotype, with ablation of B cells and antigen-presenting cells (APCs). CD40L
of autoantibodies. IRAK1 is also involved in the expression can generally be detected across hematopoietic
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pathogenesis of SS. A representative study highlighting cells. Upon interaction with CD40, B cells get activated,
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IRAK1 in SS was conducted by Zilahi et al. They found and the formation of germinal centers is stimulated. 134,135
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that while TRAF6 is overexpressed, IRAK1 gene expression These germinal centers, in turn, may induce formation of
in peripheral mononuclear cells of SS patients was lower ectopic lymphoid sites in the salivary glands of SS patients.
than healthy controls. In parallel, miR-146a/b, which may Both CD40 and CD40L were found highly expressed
target both TRAF6 and IRAK1 was overexpressed in SS in SS infiltrating mononuclear cells from salivary gland
patients compared to healthy controls. Several works tissue, presumably contributing to excess B cell activation,
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Volume 4 Issue 2 (2025) 6 doi: 10.36922/gpd.8321