# The Immunopathogenic role of XIST in Sjogren's Syndrome

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2020 · $245,625

## Abstract

Project Summary/Abstract
 Sjögren’s syndrome (SS) is a systemic autoimmune disease that predominantly affects women, yet
the mechanisms driving this strong gender bias are unknown. The X chromosome has been implicated in
the increased female susceptibility to autoimmune diseases like SS, and compelling evidence suggests that
abnormal X chromosome inactivation (XCI) may play a pathogenic role. XCI occurs during development to
normalize X-linked gene dosage between men and women in a manner dependent on the X-inactive specific
transcript (XIST), a long non-coding RNA (lncRNA). Although this is the only known function of XIST RNA,
it continues to be synthesized throughout life in individuals with two X chromosomes. A non-classical
distribution of XIST outside of the nucleus has recently been observed in a subset of B and T cells from
healthy women. The mechanisms and consequences of this non-canonical XIST expression have not been
explored, and several additional intriguing observations suggest that XIST possesses properties that may
contribute to the pathogenesis of autoimmune diseases, independently of XCI, including: 1) XIST is a
lncRNA present at high levels in individuals predisposed to the development of autoimmunity; 2) the
dominantly targeted autoantigens in SS, Ro/SSA and La/SSB, are RNA-binding proteins that can be found
in complexes with self-RNA; and 3) our analysis of the XIST RNA sequence reveals the presence of a known
TLR7-stimulatory motif. Together with growing evidence that chronic exposure to self-RNA alone or in
immune complexes can stimulate pathogenic TLR7-dependent responses, these observations support our
hypothesis that XIST RNA contributes to the female susceptibility to autoimmunity by acting as an
endogenous TLR7 agonist. We propose to build on our preliminary data to systemically examine the critical
aspects of this hypothesis through the study of human biospecimens and cellular models. In Aim 1, high-
throughput flow cytometric methods will be used to compare the expression and distribution pattern of XIST
RNA in the peripheral blood cells of men and women with SS compared to sex-matched healthy controls.
Aim 2 will examine XIST release from dying cells and potential interactions with SS autoantigens, to
determine whether XIST could be a component of circulating immune complexes in patients with SS. Finally,
in Aim 3, we will evaluate the capacity of XIST RNA to act as a TLR7 ligand. This work has the potential to
define a novel proinflammatory role for XIST in the pathogenesis of SS, which could inform the future
development of therapies that disrupt the disease promoting capacity of XIST for the treatment of SS and
related autoimmune conditions.

## Key facts

- **NIH application ID:** 9979575
- **Project number:** 1R21DE028391-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Erika Darrah
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,625
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979575

## Citation

> US National Institutes of Health, RePORTER application 9979575, The Immunopathogenic role of XIST in Sjogren's Syndrome (1R21DE028391-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9979575. Licensed CC0.

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