Nongenetic Enzyme Impairment May Facilitate Lupus Nephritis Pathogenesis

A newly discovered enzyme-inactivation pathway may help illuminate a core pathogenic mechanism.

Upon examining DNASE1L3 activity in patients with systemic lupus erythematosus (SLE), researchers found the vast majority of patients with SLE had no mutation in the DNASE1L3 gene, and more than 50 percent of patients with sporadic SLE and kidney involvement had reduced DNASE1L3 activity. ADAPTED FROM: JEM. 2021;218(5): e20201138

Researchers also found autoantibodies targeting DNASE1L3 increase: Patients with sporadic SLE also have more neutralizing autoantibodies targeting DNASE1L3, suggesting a physical—not genetic—activation. ADAPTED FROM: JEM. 2021;218(5): e20201138

Rare inherited null mutations in the DNASE1L3 gene cause childhood lupus characterized by high titers of anti-double-stranded DNA (anti-dsDNA) antibodies and renal involvement. In a study in the Journal of Experimental Medicine, researchers led by Boris Reizis, PhD, and Jill P. Buyon, MD, examined DNASE1L3 enzyme activity in a cohort of patients with severe sporadic systemic lupus erythematosus (SLE).

Their research identified a surprisingly common nongenetic disease mechanism, in which autoantibodies harbored by the patients react with the DNASE1L3 enzyme.

“Because we found that the nongenetic deficiency of this enzyme was not uncommon, we could study many of these patients and some of the mechanistic details actually became more apparent.”
Boris Reizis, PhD

“Because we found that the nongenetic deficiency of this enzyme was not uncommon, we could study many of these patients and some of the mechanistic details actually became more apparent,” Dr. Reizis says. The DNASE1L3 enzyme helps break down microparticle-associated extracellular DNA. A reduction in its activity leads to an increase in extracellular DNA, which can prompt the immune system to increase the level of dsDNA antibodies and potentially result in SLE with nephritis.

“Rare genetic mutations can put a spotlight on the protein target, and by knowing the underlying problem one may be able to apply it to a much larger population of patients,” Dr. Buyon adds.

Featured Experts

Boris Reizis, PhD

Rheumatology

Boris Reizis, PhD, is the Samuel A. Brown Professor of Medicine and a professor of pathology. He is also co-director of the Judith and Stewart Colton Center for Autoimmunity and director of the Translational Immunology Center. His research focuses on stem cells in normal hematopoiesis and leukemia; dendritic cell development and function; and mechanisms of autoimmunity.

Jill P. Buyon, MD

Lupus

Jill P. Buyon, MD, is the Sir Deryck and Lady Va Maughan Professor of Rheumatology, director of the Division of Rheumatology, co-director of the Colton Center for Autoimmunity, and director of the Lupus Center. Her research and clinical work focus on lupus, lupus-like conditions, pre-lupus, and Sjogren’s syndrome.

Nongenetic Enzyme Impairment May Facilitate Lupus Nephritis Pathogenesis

Featured Experts

Boris Reizis, PhD

Jill P. Buyon, MD

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Nongenetic Enzyme Impairment May Facilitate Lupus Nephritis Pathogenesis

Featured Experts

Boris Reizis, PhD

Jill P. Buyon, MD

Your Partner in Every Patient’s Care

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