Distinct Molecular Pathways Supporting Sjögren Disease Clusters and Disease Progression

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.