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Summary

Sjögren's disease progression involves distinct immune pathways. Interferon signaling drives early B-cell active disease, potentially shifting to proliferative pathways in high systemic activity clusters.

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Area of Science:

  • Immunology
  • Genomics
  • Autoimmune Diseases

Background:

  • Sjögren's disease (SjD) is a complex autoimmune condition with varied clinical presentations.
  • Recent research has identified distinct patient clusters within SjD based on disease activity and B-cell involvement.

Purpose of the Study:

  • To investigate blood transcriptomic signatures associated with disease progression in three defined Sjögren's disease patient clusters: B-cell active with low symptoms (BALS), high systemic activity (HSA), and low systemic activity with high symptoms (LSAHS).
  • To identify molecular pathways driving disease evolution within these clusters, particularly in an evolutive subgroup of BALS (BALS_Evol).

Main Methods:

  • Analysis of transcriptomic data from the ASSESS cohort (n=351).
  • Classification of patients into predefined SjD clusters (BALS, HSA, LSAHS) and identification of an evolutive BALS subgroup (BALS_Evol).
  • Differential gene expression analysis and Gene Set Enrichment Analysis to identify subgroup-specific transcriptomic signatures and biological pathways.

Main Results:

  • Both BALS and HSA clusters showed increased type I/II interferon (IFN)-stimulated gene expression compared to LSAHS.
  • The BALS cluster, especially BALS_Evol, exhibited heightened IFN activity and inflammatory signaling, with enrichment of IFNα/γ, TNFα, IL-6, complement, and mTORC1 pathways.
  • The HSA cluster displayed attenuated IFN and KRAS activity but activated MYC, mTOR, and oxidative phosphorylation pathways, suggesting a shift towards proliferation and metabolism.

Conclusions:

  • Interferon signaling is a key feature in both HSA and BALS Sjögren's disease clusters.
  • In BALS, IFN signaling may initiate early disease progression, which can transition to proliferative pathways associated with high systemic activity.
  • These findings offer novel insights into the molecular mechanisms underlying Sjögren's disease progression and suggest potential therapeutic targets.