February 22, 2024

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Why are women more susceptible to autoimmune diseases?

Why are women more susceptible to autoimmune diseases?



Why are women more susceptible to autoimmune diseases?

X Chromosome Inactivation Linked to Increased Risk of Autoimmune Diseases in Females, New Study Reveals.

Autoimmune diseases, ranking third in global epidemics after cancer and heart disease, affect approximately 24 to 50 million Americans, with three-quarters of them being females.

Researchers from institutions including Stanford University School of Medicine shed light on the heightened susceptibility of females to autoimmune diseases, attributing it to X chromosome inactivation.

Published on February 1, 2024, in the journal Cell, the study titled “Xist Ribonucleoproteins Promote Female Sex-Biased Autoimmunity” unravels the connection between the occurrence of autoimmune diseases and X chromosome inactivation in female mammals.

The findings not only offer insights into the reasons behind the elevated risk in females but also provide explanations for autoimmune diseases in males, paving the way for improved prediction of autoimmune disease development.

Why are women more susceptible to autoimmune diseases?


Research Background:

In mammals, females possess the XX genotype, while males have the XY genotype.

To balance gene expression between genders, females silence one of their X chromosomes in each cell through the action of long-chain non-coding RNA (lncRNA).

Xist, a crucial lncRNA, plays a key role in X chromosome inactivation (XCI), wrapping the inactive X chromosome in ribonucleoprotein complexes.

Main Research Findings:

  1. Transgenic Mice Modeling Autoimmune Diseases:

    • Researchers developed transgenic mice to simulate autoimmune diseases by inducing Xist expression in male animals.
    • The induced expression of Xist led to significant changes in T cells, resembling characteristics observed in females.
  2. Increased Severity of Disease and Immune Response Alterations:

    • Analysis of diseased animals at the single-cell transcriptome level revealed elevated levels of atypical B cells and suppressed T cell regulatory factors.
    • The severity of the disease in transgenic animals was linked to increased activity of atypical B cells and decreased immune regulatory programs in B and T cells.
  3. Autoantibodies Against XIST RNP in Autoimmune Patients:

    • Blood serum samples from patients with dermatomyositis (DM), systemic sclerosis (SSc), and systemic lupus erythematosus (SLE) exhibited strong reactions to XIST complex proteins.
    • Autoimmune patients showed a significant response to 53 proteins associated with XIST RNP, suggesting multiple components of XIST RNP as novel self-antigens.


Conclusion:

The study, led by Professor Howard Y. Chang, highlights the crucial role of Xist RNP in driving autoimmune diseases, particularly emphasizing its impact on females.

By inducing transgenic Xist RNP formation in male animals, the researchers successfully observed increased disease severity and heightened autoimmune lymphocyte signaling pathways.

The findings underscore the importance of considering Xist RNP in understanding gender biases in autoimmune diseases, providing a foundation for better predictive measures before the onset of autoimmune conditions.

Why are women more susceptible to autoimmune diseases?

References:

1. Dou et al., Xist ribonucleoproteins promote female sex-biased autoimmunity, Cell (2024).
2. Yu, B., et al., (2021). B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells. Cell 184, 1790–1803.e17.
3. Moulton, V.R. (2018). Sex Hormones in Acquired Immunity and Autoimmune Disease. Front. Immunol. 9, 2279.

(source:internet, reference only)


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