Profiling Shared Cytotoxic Immune Signatures in SLE-Associated Coronary Injury Through Transcriptomics and Machine...

Area of Science:

• Immunology
• Cardiovascular Disease
• Genomics

Background:

• Systemic lupus erythematosus (SLE) is an autoimmune disease with increased risk of cardiovascular complications.
• Coronary artery disease (CAD) shares inflammatory pathways with autoimmune conditions.
• Understanding shared molecular mechanisms is crucial for managing SLE-associated cardiovascular risk.

Purpose of the Study:

• To investigate shared molecular pathways between SLE and CAD.
• To identify mechanisms of coronary injury in SLE patients.
• To uncover potential diagnostic biomarkers for SLE-related coronary complications.

Main Methods:

• Analysis of bulk transcriptomic datasets for SLE and CAD.
• Identification of differentially expressed genes (DEGs), immune cell infiltration, and co-expression networks.
• Construction and validation of a diagnostic model using external cohorts and machine learning.
• Single-cell RNA-seq analysis for cellular localization and intercellular communication.
• Quantitative PCR (qPCR) validation in patient samples.

Main Results:

• Identified 146 common DEGs enriched in immune pathways related to cell toxicity.
• Found shared dysregulation in cytotoxic lymphocytes, including natural killer (NK) cells and CD8+ T cells.
• Pinpointed 11 hub genes, with GZMK and KLRK1 highlighted as core genes by machine learning.
• Developed a diagnostic model with strong performance for SLE and CAD.
• Validated GZMK and KLRK1 for diagnostic utility in SLE-related coronary injury.
• Confirmed higher expression of GZMK and KLRK1 in blood cells of SLE patients with CAD.

Conclusions:

• SLE and CAD share a cytotoxic lymphocyte-driven molecular axis.
• GZMK/KLRK1-mediated immune dysregulation contributes to coronary injury in SLE.
• GZMK and KLRK1 show promise as biomarkers for early detection and risk stratification of SLE-associated coronary complications.
• Further validation in larger cohorts is warranted, especially for specific subgroups like coronary microvascular dysfunction.