Xist ribonucleoproteins promote female sex-biased autoimmunity

Dou, Diana R.; Zhao, Yanding; Belk, Julia A.; Zhao, Yang; Casey, Kerriann M.; Chen, Derek C.; Li, Rui; Yu, Bingfei; Srinivasan, Suhas; Abe, Brian T.; Kraft, Katerina; Hellström, Ceke; Sjöberg, Ronald; Chang, Sarah; Feng, Allan; Goldman, Daniel W.; Shah, Ami A.; Petri, Michelle; Chung, Lorinda S.; Fiorentino, David F.; Lundberg, Emma K.; Wutz, Anton; Utz, Paul J.; Chang, Howard Y.

doi:10.1016/j.cell.2023.12.037

Cited by 54 publications

(26 citation statements)

References 97 publications

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“…In particular, the X-chromosome has emerged as a potential common target of diverse factors driving SLE pathogenesis. Consistent with this hypothesis, auto-antibodies to the X-chromosome inactivating gene XIST 24 and escape from X-Chromosome Inactivation (XCI) 25 have been implicated in SLE pathogenesis and may explain the predominance of women in SLE 25,26 . Here, our findings identify a potential link between the inflammatory-feedback and X-chromosome hypotheses.…”

Section: Lntroductionmentioning

confidence: 81%

Unsupervised generative AI discovers pan-leukocyte dysregulated pathways in single-cell lupus data

Bolouri,

Cerosaletti,

Lacy-Hulbert

2024

Preprint

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Comparisons of single-cell RNA-sequencing (scRNA-seq) data from healthy and diseased tissues are widely used to identify cell-type-specific dysregulated genes, pathways, and processes. Accordingly, many sophisticated methods have been developed for this purpose. However, such tools generally require considerable user expertise for optimal performance. Here, we show that unsupervised application of a linearly-decoded Variational Auto Encoder (a generative AI model) to scRNA-seq data recapitulates and extends findings from a seminal recent lupus study and leads to new insights. Thanks to existing software libraries, our approach is straightforward to implement, computationally efficient, methodologically robust, and produces consistent and reproducible results.

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Section: Lntroductionmentioning

confidence: 81%

Unsupervised generative AI discovers pan-leukocyte dysregulated pathways in single-cell lupus data

Bolouri,

Cerosaletti,

Lacy-Hulbert

2024

Preprint

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“…The XX karyotype constitutes an additional risk for autoimmune diseases, independent of hormonal status. In particular, mechanisms associated with X chromosome inactivation, which are absent in males, trigger antigenic responses ( 61 ). Despite the increased risk of autoimmune diseases in females, we did not observe differences in B cell development between male and female mice in our current study.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupts immune cell homeostasis

Demkova,

Bugajev,

Adamcova

et al. 2024

Front. Immunol.

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ORMDL3 is a prominent member of a family of highly conserved endoplasmic reticulum resident proteins, ORMs (ORM1 and ORM2) in yeast, dORMDL in Drosophila and ORMDLs (ORMDL1, ORMDL2, and ORMDL3) in mammals. ORMDL3 mediates feedback inhibition of de novo sphingolipid synthesis. Expression levels of ORMDL3 are associated with the development of inflammatory and autoimmune diseases including asthma, systemic lupus erythematosus, type 1 diabetes mellitus and others. It has been shown that simultaneous deletions of other ORMDL family members could potentiate ORMDL3-induced phenotypes. To understand the complex function of ORMDL proteins in immunity in vivo, we analyzed mice with single or double deletions of Ormdl genes. In contrast to other single and double knockouts, simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupted blood homeostasis and reduced immune cell content in peripheral blood and spleens of mice. The reduced number of splenocytes was not caused by aberrant immune cell homing. A competitive bone marrow transplantation assay showed that the development of Ormdl1-/-/Ormdl3-/- B cells was dependent on lymphocyte intrinsic factors. Highly increased sphingolipid production was observed in the spleens and bone marrow of Ormdl1-/-/Ormdl3-/- mice. Slight, yet significant, increase in some sphingolipid species was also observed in the spleens of Ormdl3-/- mice and in the bone marrow of both, Ormdl1-/- and Ormdl3-/- single knockout mice. Taken together, our results demonstrate that the physiological expression of ORMDL proteins is critical for the proper development and circulation of lymphocytes. We also show cell-type specific roles of individual ORMDL family members in the production of different sphingolipid species.

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“…A recent study showed that generation of an inducible and non-silencing (repeat A mutant) XIST transgenic overexpressing male mouse resulted in the formation of autoantibodies against XIST associated proteins or ribonucleoproteins (RNPs). These autoantibodies are found in human systemic lupus patient samples also [ 44 ]. The adaptive immune repertoire of T and B cells in addition to the chromatin states of these male transgenic mice more closely resembled that of wild type females [ 44 ].…”

Section: Architectural Lncrnas Regulate Gene Expression By Modulating...mentioning

confidence: 99%

“…These autoantibodies are found in human systemic lupus patient samples also [ 44 ]. The adaptive immune repertoire of T and B cells in addition to the chromatin states of these male transgenic mice more closely resembled that of wild type females [ 44 ]. Given that the presence of these resulted in increased disease severity in the mouse models of SLE suggests that these novel autoantigens indeed contribute to the disease pathogenesis in models of SLE and in human patients suffering from SLE.…”

Section: Architectural Lncrnas Regulate Gene Expression By Modulating...mentioning

confidence: 99%

LncRNAs, nuclear architecture and the immune response

Montano,

Flores-Arenas,

Carpenter

2024

Nucleus

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Long noncoding RNAs (LncRNAs) are key regulators of gene expression and can mediate their effects in both the nucleus and cytoplasm. Some of the best-characterized lncRNAs are localized within the nucleus, where they modulate the nuclear architecture and influence gene expression. In this review, we discuss the role of lncRNAs in nuclear architecture in the context of their gene regulatory functions in innate immunity. Here, we discuss various approaches to functionally characterize nuclear-localized lncRNAs and the challenges faced in the field.

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Xist ribonucleoproteins promote female sex-biased autoimmunity

Cited by 54 publications

References 97 publications

Unsupervised generative AI discovers pan-leukocyte dysregulated pathways in single-cell lupus data

Unsupervised generative AI discovers pan-leukocyte dysregulated pathways in single-cell lupus data

Simultaneous deletion of ORMDL1 and ORMDL3 proteins disrupts immune cell homeostasis

LncRNAs, nuclear architecture and the immune response

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