LRA-Funded Research Helps Illuminate Genetic Causes of Lupus
LRA-Funded Research Helps Illuminate Genetic Causes of Lupus

October 19, 2021

Two recent studies funded in part by the Lupus Research Alliance offer a new, more detailed understanding of the genetic causes of lupus as well as potential therapy approaches. One study shows a potential mechanism for how a variant for the gene neutrophil cytosolic factor 1 (NCF1) may lead to systemic lupus erythematosus (SLE). Another study explains how the gene called interleukin 10 (IL-10) becomes overactive in lupus patients. Both studies were directed by Dr. Betty Tsao, the Professor and Richard M. Silver Endowed Chair for Inflammation Research, at the Medical University of South Carolina.

When the Immune System Can’t Do its Job

The first study, published in the journal Annals of the Rheumatic Disease suggests that a variant of the gene NCF1 affects the ability of the immune system to remove dying or dead cells. Normally, a type of immune cell, called a macrophage, is responsible for the removal of dead or dying cells from the body. However, when dead cells are not removed in a timely manner, this can cause autoinflammation which can lead to autoimmune diseases such as SLE.

Dr. Tsao and colleagues sought to understand how mice with a variant of gene NCF1 that functions less efficiently developed a lupus-like condition. They discovered that these mice had defective macrophages that could not properly remove dead cells; this caused an increase in the frequency of occurrence of a specific subset of helper T lymphocytes that could promote autoantibody production and the development of lupus-like kidney disease. The investigators showed that their findings in mice could be confirmed in patients affected with lupus, and lupus patients carrying two copies of this risk variant had a higher risk to develop kidney damage.  These results show that finding a way either to restore the ability of macrophages to remove dead cells or to prevent the expansion of the specific helper T lymphocytes in lupus patients might be an effective therapeutic strategy.

Too Much of a Good Thing Turns Bad

The second study, published in the journal Arthritis & Rheumatology  looked at how a gene called IL-10 becomes over-activated in lupus patients. Lupus patients have increased levels of IL-10 that are thought to support the production of damaging autoantibodies, which attack the body’s own tissues and organs.

While healthy individuals have IL-10 producing B cells to regulate the immune system, Dr. Tsao and colleagues found lupus patients have elevated  IL-10 producing B cells poised to become plasmablasts, which can lead to the development of disease-causing antibody-producing cells. They found that in SLE patients, IL-10 accumulates in B cells because the regulators that control its activity — a gene called E2F2 and a molecule called miR-17-5p – are not working properly. This finding suggests that modifying the activity of this gene and molecule may help normalize IL-10 production in SLE patients.

Both studies provide novel information about the genetic causes of lupus. These two studies also suggest new ways for treating lupus that could allow for better management of this disease.

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