April 11, 2019

The bacteria that cause urinary tract infections may trigger lupus flares, a former Alzheimer’s disease therapy has shown promising results in research models—these are just some of the findings presented by Lupus Research Alliance-funded scientists at the 13^th International Congress on Systematic Lupus Erythematosus (LUPUS 2019), held in San Francisco. Here are some of their discoveries.

A New Way to Halt Lupus Flares
The LRA-funded work by Dr. Roberto Caricchio of the Lewis Katz School of Medicine at Temple University and colleagues suggests that antibiotics may stop disease flares. Their study indicates that bacteria responsible for urinary tract infections may spark flares or even trigger lupus.

In lupus, the immune system attacks patients’ own tissues. These attacks may occur because the tissues carry molecules that resemble the molecules of certain bacteria. Patients with lupus are susceptible to urinary tract infections, most of which are caused by bacteria that normally live in our intestines. These microbes release protein fibers called curli that can trap DNA and stimulate the immune system. Dr. Caricchio and his colleagues discovered that curli worsen lupus symptoms in animal models.

To find out whether curli had the same effect in people, the researchers obtained blood samples from patients with lupus at the Temple Lupus Clinic and tested them for antibodies, defensive molecules produced by the immune system. The scientists found that levels of antibodies that target curli were higher among people with lupus than among those without the disease. And of those with lupus, antibodies that recognize curli were more abundant in people who were undergoing flares. Treating patients with antibiotics to kill the bacteria that cause urinary tract infections may prevent flares, the researchers concluded.

Reviving an Old Drug to Treat Lupus
Results from a team led by Dr. Mariana Kaplan of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), also point to a possible treatment for lupus—a drug originally developed as a therapy for Alzheimer’s disease.

The drug, idebenone, was not effective against Alzheimer’s disease. But Dr. Kaplan and her colleagues reasoned that it might work against lupus. In patients with the disease, mitochondria, the structures that serve as power plants for cells, malfunction. They release large amounts of damaging molecules known as reactive oxygen species and produce less energy. Idebenone neutralizes reactive oxygen species and can increase mitochondria’s power-generating ability.

The scientists tested idebenone in animals with lupus-like symptoms. The animals that received idebenone survived longer and suffered less kidney damage, a common problem in patients with lupus. Their mitochondria also performed better, and the animals showed less damage from reactive oxygen species. Future studies could include testing this drug in clinical trials in lupus.

Profiling Immune Cells in the Kidneys
Dr. Deepak Rao of Harvard Medical School and colleagues provided a detailed and comprehensive look at the immune cells that invade and damage the kidneys in patients with lupus. The results could help researchers design new treatments for lupus nephritis, the kidney inflammation that affects about half of patients with the disease. Their work was part of the Accelerating Medicines Partnership, which the LRA co-sponsors.

The immune cells that swarm into the kidneys can harm the organs so badly that they stop working. To create new drugs to prevent this damage, researchers need to better understand which cells are entering the kidneys and what effects they produce. The Accelerating Medicines Partnership enabled Rao and his colleagues to profile the immune cells in kidney tissue samples from more than a dozen medical centers around the United States.

The scientists found more kinds of immune cells in the kidneys than they expected. For instance, they identified three varieties of the cell-killers known as cytotoxic T cells, which suggests each type may have a different role in lupus nephritis. Now, the researchers plan to focus on unraveling how each type of cell contributes to lupus nephritis.

Lupus May Impair the Lymphatic System
With her grant from the Lupus Research Alliance, Dr. Theresa Lu, Dr. Noa Schwartz and other colleagues at the Hospital for Special Surgery performed one of the first studies to identify how lupus changes the lymphatic system, the network of tubes that transports fluid and immune cells around the body. They discovered that in animals with lupus, lymphatic circulation slows down, which may explain why patients with the disease often develop severe skin inflammation.

The lymphatic system has an important effect on the immune system because it helps control inflammation and the activities of immune cells.  Researchers have shown that the lymphatic circulation is abnormal in autoimmune diseases such as rheumatoid arthritis, , but how the lymphatic system responds in lupus is not clear.

Dr. Lu and her team used a blue dye to follow lymph movement in animal models with ear inflammation. When the inflammation was in its early stages, the flow of lymphatic fluid from the ears surged in all of the animals, whether they had lupus or not. Over time, the rate of flow continued to increase in healthy animals, but it stopped rising in those with lupus. Because less fluid is draining from the animals’ ears, molecules produced by immune cells might become trapped and continue to spur inflammation. The same thing may occur in the skin of patients with lupus.

Identifying Genes Responsible for High Interferon Levels
Patients with lupus usually produce too much of the proteins known as type I interferons, which stimulate the immune system. A team led by Dr. Timothy Niewold of NYU School of Medicine found that a version of the gene PNP found in 20% to 30% of the population may promote high interferon levels. The discovery could eventually allow tailored treatments for patients who carry this version of the gene.