How Lupus Antibodies Sabotage a Key Enzyme — and What It Means for Treating Kidney Disease

A study published in the Journal of Experimental Medicine by researchers at NYU Langone Health — supported by the Colton Center for Autoimmunity — has identified a previously underappreciated, non-genetic mechanism that may contribute to lupus nephritis in a significant proportion of patients. The findings open a new avenue for biomarker development and potential therapeutic intervention.

The study centers on an enzyme called DNASE1L3, which is responsible for breaking down a specific type of cell-free DNA — the DNA contained within microparticles released by dying cells. When this enzyme is absent or inactive, that microparticle-associated DNA accumulates and becomes visible to the immune system, triggering the production of anti”double-stranded DNA (anti-dsDNA) antibodies that are a hallmark of lupus nephritis.

While rare inherited mutations in the DNASE1L3 gene were already known to cause a severe form of childhood lupus, the NYU research team — led by Professor Boris Reizis and Dr. Jill Buyon, both co-directors of the Colton Center — found something unexpected: more than 50 percent of a patient cohort with sporadic lupus nephritis showed significantly reduced DNASE1L3 activity, despite having no genetic mutations. Further analysis revealed that neutralizing autoantibodies targeting the enzyme itself were responsible for physically inactivating it — a non-genetic mechanism converging on the same pathogenic pathway.

The researchers now plan to investigate whether declining DNASE1L3 activity might serve as a predictive biomarker for kidney disease onset, and whether restoring enzyme function could offer a new therapeutic strategy for lupus patients.