Last week we gave you only half the story of what scientists funded by the Lupus Research Alliance (LRA) shared at 2019 ACR/ARP. So many studies were presented that we needed to bring you Part 2 to expand our coverage of the major discoveries your donations have made possible. And a Part 3 is yet to come.
Dr. Eric Morand of Monash University in Australia and colleagues reported new details about how a possible drug target reduces lupus symptoms.
Steroids are standard treatments in lupus because they work well but can cause diabetes, heart disease, and other serious side effects. Some of their benefits may come from their effect on a protein called GILZ that reduces inflammation, but people with lupus often make less GILZ than those without the disease. To find out more about how GILZ works, Dr. Morand and his team analyzed lupus-prone mice that lack the protein. Funded by LRA, their results suggest that GILZ reduces inflammation by blocking the effects of molecules called type I interferons that help drive lupus symptoms.
The immune system attacks patients’ tissues in lupus. One kind of immune cell involved in these attacks are plasmocytoid dendritic cells (pDCs), which early in the disease produce large amounts of the Type I interferons which contribute to active disease. The other is switched memory B cells, which appear later and serve as “rapid responders” each time the immune system “gears” up to respond to a threat it encountered before. However, there could be different varieties of these cells, some of which might be more harmful than others
With their grant from the LRA, Dr. Timothy Niewold of the NYU School of Medicine and colleagues set out to find out if there are different kinds of plasmacytoid dendritic cells and switched memory B cells. They analyzed which genes were switched on or off in more than 5,000 cells from patients with lupus and people who didn’t have the disease. They found that there are several different types of plasmacytoid dendritic cells and switched memory B cells in patients with lupus. Some of these types may have more important roles in the disease and could make better targets for new drugs.
Scientists aimed to resolve a long-standing paradox. On the one hand, the release of special proteins known as complement, is one of the body’s defenses for eliminating bacteria and damaged cells. However, in lupus patients, complement proteins along with autoantibodies have been found to promote kidney damage. But on the other hand, people are also more likely to develop lupus if they have low levels of these proteins.
With their LRA funding, Dr. Keith Elkon of the University of Washington, Seattle, and his colleagues may have solved this apparent conflict. They found that mice that lack two key proteins in the system still developed kidney damage and other features of lupus. Dr. Elkon and his team discovered that the mice used different mechanisms to produce other complement proteins that lead to kidney damage, suggesting that new drugs that target these mechanisms are possible lupus therapies.
A study by Dr. Boris Reizis shed light on a particular pathway that may cause lupus. Some patients whose family members also have lupus inherit a defective gene that prevents them from making a protein called DNASE1L3. This protein normally helps destroy DNA that is released by dying cells in the body. The lack of DNASE1L3 causes a buildup of cellular “trash” which triggers the immune system to attack a patient’s own healthy cells and tissues. However, researchers determined to find out if DNASE1L3 protein was faulty in SLE patients who don’t have the defect in the DNASE1L3 gene.
Dr. Boris Reizis of the NYU Langone Medical Center and colleagues studied patients with SLE who had a normal DNASE1L3 gene and found that the protein wasn’t working well in some of them. Many of these patients made antibodies to the DNASE1L3 protein which could still prevent the protein from working as it should. Their study shows that even in people who don’t inherit a defective version of the gene for DNASE1L3, the protein may not work properly and may promote development of lupus.
“Each of these studies point to potential targets for development of new treatments,” commented Teodora Staeva, PhD, Chief Scientific Officer at the Lupus Research Alliance. “We look forward to further study to see which are viable for clinical development.”