Objective:

To explore the role of cell-free DNA (cfDNA) in systemic lupus erythematosus (SLE), focusing on its molecular characteristics as biomarkers and its contribution to disease mechanisms.

Approach:

Key Findings:

• cfDNA is released during cell death and can promote immune activation in SLE.
• Molecular characteristics of cfDNA, such as fragment length, end motifs, jaggedness, and epigenetic modifications, serve as biomarkers of disease activity.
• Deficiencies in DNASE1L3 alter cfDNA fragmentation and enhance type I interferon signaling, driving B-cell differentiation and anti-dsDNA antibody production.
• Autoantibodies can neutralize DNASE1L3, impeding DNA clearance and exacerbating inflammation.

Interpretation:

cfDNA plays a dual role as both a disease mediator and a diagnostic tool in SLE.

Limitations:

• The study emphasizes the need for large-scale validation and standardization of cfDNA biomarkers for clinical application.

Conclusion:

The findings support the ongoing development of therapies targeting type I interferon and plasmacytoid dendritic cells.

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