Mapping systemic lupus erythematosus heterogeneity at the single-cell level

Area of Science:

• Immunology
• Genomics
• Computational Biology

Background:

• Systemic lupus erythematosus (SLE) exhibits a complex blood transcriptome.
• The cellular origins of SLE's transcriptional signatures remain unclear.

Purpose of the Study:

• To identify the specific cell types and subpopulations responsible for the SLE transcriptome.
• To investigate the link between these cellular signatures and SLE disease activity.

Main Methods:

• Single-cell RNA sequencing of ~276,000 peripheral blood mononuclear cells (PBMCs) from 33 children with SLE and 11 controls.
• Analysis of ~82,000 PBMCs from adults with SLE.
• Identification of interferon-stimulated gene-high (ISG-high) signatures and associated subpopulations.

Main Results:

• Increased ISG expression was observed in cells from children with SLE compared to controls.
• ISG-high signatures originated from specific subpopulations within monocytes, T cells, NK cells, dendritic cells, B cells, and plasma cells.
• Expansion of ISG-high and/or monogenic lupus-associated gene-enriched subpopulations correlated with higher SLE disease activity in both children and adults.

Conclusions:

• This study resolves the cellular origin of SLE transcriptional signatures.
• Identified subpopulations provide insights into SLE heterogeneity and disease severity.
• Findings pave the way for precision medicine approaches in SLE treatment.