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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2024)

Autoimmune disease arises from dysregulation of the immune system, leading to its attack on the body's own tissues and organs. The clinical heterogeneity of these diseases arises from several sources, such as genetic predisposition, environmental triggers, and aberrant immune responses. One emerging area of interest is the role of transposable elements (TEs) in autoimmune disease pathogenesis because these self-nucleic acids can be mistakenly detected as foreign, which can trigger a chronic immune reaction.There is growing appreciation for the role of TEs in systemic lupus erythematosus (SLE) and studies have found differentially expressed TEs in SLE patients, which suggests a link between TE activity and disease mechanisms. Our work investigated TE expression in four immune cell types from SLE patients, revealing cell-specific and SLE subphenotype-specific differentially expressed TEs, with additional cell-type-specific TE associations in different ancestry groups. TE expression was also associated with host gene expression involved in antiviral and immune responses, supporting the hypothesis that TEs could activate the innate immune system and contribute to chronic inflammation and autoimmunity. This study underscores the importance of TEs in SLE heterogeneity and highlights the need for further exploration of TE expression in normal immune cells and functional studies to understand their role in SLE pathogenesis. Future work to study whether antiretroviral drugs could reduce expression of TEs and mitigate SLE symptoms is warranted, given the potential involvement of TEs in autoimmune disease pathogenesis

    Cover page: Integrative Precision Medicine Approach to Dissect Patient Heterogeneity in Systemic Lupus Erythematosus
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2024)

    Objective

    There is an established yet unexplained link between interferon (IFN) and systemic lupus erythematosus (SLE). The expression of sequences derived from transposable elements (TEs) may contribute to SLE phenotypes, specifically production of type I IFNs and generation of autoantibodies.

    Methods

    We profiled cell-sorted RNA-sequencing data (CD4+ T cells, CD14+ monocytes, CD19+ B cells, and natural killer cells) from peripheral blood mononuclear cells of 120 patients with SLE and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes, including autoantibody production and disease activity.

    Results

    We found 731 differentially expressed (DE) TEs across all SLE phenotypes that were mostly cell specific and phenotype specific. DE TEs were enriched for specific families and open reading frames of viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity, such as LY6E, ISG15, and TRIM22, and pathways such as IFN signaling.

    Conclusion

    These findings suggest that expression of TEs contributes to activation of SLE-related mechanisms in a cell-specific manner, which can impact disease diagnostics and therapeutics.
      Cover page: Cell‐Specific Transposable Element and Gene Expression Analysis Across Systemic Lupus Erythematosus Phenotypes
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