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

arthritis and autoimmune thyroid disease compared to responses. On ligation with the target, TLR7 can signal
healthy controls. 25,83 Patients affected with scleroderma the production of proinflammatory cytokines. Through
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also exhibited skewed XCI in blood cells. Interestingly, IRF7, TLR7 can also trigger production of Type I IFN by
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divergent patterns across different diseases highlight dendritic cells. Several studies have characterized the role of
the biological complexity of this phenomenon as well as TLR7 in the pathogenesis of SLE. TLR7 genetic mutations,
possible inter-individual variability across autoimmune including gain-of-function mutations, have been reported
conditions. 85,86 As a representative example, a recent are a cause of SLE. 96-98 Recent works identified a mutation
work found reduced XCI-skew in females affected with in UNC93B1 – a TLR7 trafficking factor that interacts
SLE compared to controls. These variations may reflect with ARL8B to regulate intracellular levels of TLR7 – as a
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distinct molecular mechanisms at play within different possible cause of childhood SLE. Specifically, the mutation
ADs, including heterogenous, cell-type specific impact on results in aberrant interaction with the BORC complex,
XCI-skew. ADs are characterized by excessive systemic or which in turn leads to elevated endosomal TLR7 levels,
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localized inflammation, often accompanied by proliferation triggering excessive immune stimulation. Single-cell
of specific cell types. Autoreactive T-cells that evade resolution analyses revealed that in XX cells and 47, XXY
immune system’s tolerance in the thymus during early cells, TLR7 escapes XCI in B lymphocytes, monocytes,
development may proliferate and differentiate both before and plasmacytoid dendritic cells. Cells with biallelic TLR7
and during autoimmune responses. For instance, in both dosages also exhibited significantly greater potential of
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murine models and human cases of SLE, hematopoietic immunoglobulin G class switching. These data support
stem and progenitor cells exhibit substantial expansion and a role of TLR7 escape, as well as other X-linked processes
enhanced differentiation potential on inflammation. 88,89 capable of modulating TLR7 dosages, including XCI-skew,
Distinct T-cell subsets, including regulatory T-cells, can in ADs pathogenesis. A recent study found increased TLR7
also clonally expand upon stimulation in autoimmune expression in salivary glands of SS patients compared to
responses. Similarly, synovial fibroblasts, macrophages, healthy individuals. TLR8 KO mice develop SLE but also
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and Th cells proliferate and differentiate in the synovium a SS-like pathology with ectopic lymphoid aggregates.
in patients with rheumatoid arthritis. Therefore, due Interestingly, when abrogating also TLR7 in TLR8 KO
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to enhanced cell proliferation, it is entirely possible that mice, the SS-like phenotypes are reduced, thus indicating
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skewed XCI patterns in hematopoietic and immune cells an important role for TLR7 in the pathogenesis of SS.
could arise, to some extent, as a consequence of ADs. TLR7 protein levels were found to be significantly higher
in peripheral blood mononuclear cells (PBMCs) from
Another proposed mechanism involves increased 102
functional dosage of X-linked genes following X-linked SS patients than healthy controls. Another study
documented the presence of TLR7- and TLR9-positive
reactivation. Epigenetic alterations of the inactive X cells in ductal epithelial cells, epithelial islands, and
chromosome may lead to the expression of genes that are lymphocytes of the parotid glands in patients affected
typically silent, thereby contributing to autoimmunity. This with primary SS. More details at the cellular levels were
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hypothesis is bolstered by recent findings demonstrating obtained from another study, showing upregulation of
that perturbations of XCI can reactivate X-linked genes, TLR7, but not TLR9, in IFN+ plasma dendritic cells and
such as TLR7, in B cells, dendritic cells, and macrophages, monocytes isolated from PBMCs from SS patients.
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with subsequent manifestation of lupus-like disease in Notably, TLR7 expression levels were found positively
mice. Earlier studies have also indicated that reactivation correlated with CXCR5, CXCL13, and TNF in salivary
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of the silent X chromosome may contribute to SLE through glands of primary SS patients. As age is a risk factor of SS,
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the expression of CD40L in T cells, suggesting that specific it is also possible that TLR7 activity is deregulated in age-
epigenetic changes could act as pathogenetic drivers. 93
associated B-cells (ABCs). ABCs arise with age, expand
The X chromosome harbors numerous immune-related in ADs, and can produce autoantibodies. The role of
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factors, such as TLR7/8, CD40L, IRAK, and FOXP3 – key ABCs in pathogenesis of AD is not yet clear. Possibly,
players in innate and adaptive immune responses – and TLR7 is also active in ABCs likewise in other immune
BTK and IL2RG, implicated in the development of immune cell types, triggering production of autoantibodies and so
cells. Below, we will discuss a set of X-linked genes that exacerbating the risk of SS with aging. Altogether, these
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have been associated with ADs. and other data support an important role for TLR7 in
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TLR7 encodes for a member of the TLR family, which the etiology and progression of SS.
plays crucial roles in pathogen recognition and activation CXorf21 (Chromosome X open reading frame 21;
of innate immunity. TLR7 is capable of recognizing ssRNA also known as TASL) gene is located on the short arm of
oligonucleotide sequences and triggering innate immune the X chromosome and encodes for a protein involved

Volume 4 Issue 2 (2025) 5 doi: 10.36922/gpd.8321