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

production of autoantibodies, and inflammation, Sera are needed to fully characterize the influence of XCI-skew
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from SS patients is also rich in soluble CD40L, further and XCI escape on the risk of ADs. On the other end,
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supporting the notion that both B and T cells are involved understanding the exact molecular mechanisms by which
in SS pathogenesis. The activity of CD40 and CD40L ADs impact X-chromosome biology, including XCI-skew
also includes stimulation of proinflammatory cytokine and XCI escape, deserves further studies. While this review
production, that is, TNF-α and IFN-γ, in lymphoid cells. discusses a set of major ADs – systemic lupus erythematosus,
Collectively, this enhances the inflammatory milieu in Sjögren’s syndrome, and Hashimoto’s thyroiditis – along
ADs. The increased B cell activation and proliferation with several X-linked genes implicated in sex-biased ADs,
stimulated by the CD40/CD40L pathway could also there are numerous other sex-biased ADs, as well as other
mediate a higher risk of lymphoma, which is a distinctive known X-linked genes with documented roles in ADs.
trait of SS when compared to other ADs. The CD40- Furthermore, future studies will likely uncover additional
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CD40L axis is likely to be central in many autoimmune X-linked genes involved in ADs. In particular, genes that
conditions, including to SLE pathogenesis. 138,139 For escape XCI are of great importance in understanding the
instance, CD40L is highly expressed in CD4+ and CD8+ pathogenetic processes underlying autoimmune traits, and
T cells from SLE patients. 138,140,141 Flow cytometry assay may serve as target for translational research, including
revealed that peripheral monocytes expressing CD40L are precision medicine approaches aimed at correcting altered
significantly more frequent in SLE patients compared to gene dosages. A comprehensive understanding of the
healthy subject, indicating the involvement of myeloid molecular factors underlying sexual dimorphisms in ADs
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cells. CD40L could also be involved in complications is essential for developing targeted, sex-specific healthcare
from SLE. An earlier study reported that transgenic plans within the framework of personalized medicine.
mouse models overexpressing CDL40 can also manifest Such an approach would account for all known biological
glomerulonephritis following SLE-like symptoms. 143 differences between the sexes, ultimately leading to more

5. Concluding remarks effective prevention, diagnosis, and treatment strategies.
This review explores the prominent roles of the Acknowledgments
mammalian X chromosome in ADs. ADs are complex, None.
heterogeneous disorders. Presumably, the interplay
between genetic factors, hormonal influences, and Funding
environmental/lifestyle exposures ultimately impact the None.
gender differences in immune system functioning at both
cellular and organismal levels. The X chromosome is a Conflict of interest
model in medical genetics and is of particular scientific
interest in the study of ADs. Being rich in immune-related The authors declare they have no competing interests.
genes and differentially inherited between the male and
female sex, it plays crucial roles in genetic inheritance and Author contributions
disease predisposition. Females benefit from having two Conceptualization: All authors
X chromosomes. X-linked genetic mutations may cause Writing–original draft: All authors
complete functional loss in males but not in heterozygous Writing–review & editing: All authors
females, where a normal gene copy residing on the wild-
type X-allele may still ensure partial functional dosages. Ethics approval and consent to participate
However, the presence of two X chromosomes also Not applicable.
correlates with an increased risk of developing ADs, with
are generally more prevalent in females. As highlighted Consent for publication
throughout this review, the functional dosage of X-linked
immune-related factors is fundamentally influenced by Not applicable.
the unique biology of the X chromosome itself. Central Availability of data
to this process are the highly regulated mechanisms of
X-inactivation, skewed X-inactivation, and escape from Not applicable.
X-inactivation. Altogether, these mechanisms contribute
to modulating immune-related processes in time and References
space, impacting sex differences in both immune responses 1. Pisetsky DS. Pathogenesis of autoimmune disease. Nat Rev
and risk of developing ADs. Clearly, more investigations Nephrol. 2023;19(8):509-524.

Volume 4 Issue 2 (2025) 7 doi: 10.36922/gpd.8321