Cutaneous Lupus Features Specialized Stromal Niches and Altered Retroelement Expression

Area of Science:

• Immunology
• Dermatology
• Genomics

Background:

• Cutaneous lupus erythematosus (CLE) is a chronic autoimmune skin disease characterized by inflammation, skin lesions, and hair loss.
• The precise mechanisms driving CLE pathogenesis, particularly the role of specific cell types and genetic elements, remain incompletely understood.

Purpose of the Study:

• To elucidate the cellular and molecular pathophysiology of cutaneous lupus.
• To investigate the association between retroelement expression and interferon signaling in lupus skin.
• To evaluate the impact of anifrolumab treatment on these pathways.

Main Methods:

• Single-cell RNA sequencing and spatial transcriptomics were employed on lesional and nonlesional skin from CLE patients and healthy controls.
• Pathway enrichment analysis and differential gene expression were performed.
• Correlation analysis between retroelement expression and interferon-stimulated genes was conducted.

Main Results:

• Lesional keratinocytes showed heightened responses to interferon-I (IFN-I), interferon-II (IFN-II), and tumor necrosis factor (TNF), alongside apoptotic signaling.
• Unique lupus-specific fibroblasts were identified, potentially contributing to inflammation and fibrosis.
• Increased retroelement expression, particularly L2b, correlated with IFN-stimulated genes across multiple cell types.
• Elevated expression of RIG-I and cGAS-STING pathway genes, involved in nucleic acid sensing, was observed.
• Anifrolumab treatment in active CLE patients downregulated RIG-I, cGAS-STING pathways, and L2b retroelement expression.

Conclusions:

• IFN-I-mediated pathways are central to cutaneous lupus immunopathology.
• Retroelement expression is significantly associated with interferon signatures in CLE skin.
• Targeting IFN-I pathways, as with anifrolumab, may modulate key inflammatory and retroelement-driven mechanisms in cutaneous lupus.