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Promising Results Funded by Lupus Research Alliance Presented at American College of Rheumatology Annual Meeting

November 17, 2016

Modifying current malaria treatments to improve lupus treatment… Cells with indigestion may be key culprits … These are just two of the exciting results researchers funded by the Lupus Research Alliance presented this week at the American College of Rheumatology annual meeting in Washington, D.C.

Making New Drugs from Old
Malaria is caused by microscopic parasites that bore into our blood cells, so it might seem to have little in common with lupus. But despite many side effects, antimalarial drugs such as Plaquenil and Mepacrine have long been standard treatments for the disease. Keith Elkon, MD, of the University of Washington in Seattle and his colleagues believed they can improve these drugs.

Funded by the Lupus Research Alliance, the team used computer analysis and experiments on cells to gauge the effectiveness of several antimalarial compounds, including Plaquenil and Mepacrine . Lupus patients’ immune systems mistakenly attack their own DNA, and the researchers tested the drugs’ ability to block a cellular alarm system that misidentifies the DNA as a threat. The team then tweaked the drugs to improve their performance. One of the upgraded compounds, X6, was powerful but less toxic and showed promising results in ‘proof of principle’ therapy  in mice. “New antimalarial drugs that could be more effective than Plaquenil may be on the horizon,” says Elkon.

Cell Corpses Get Stuck in the Craw
The billions of cells that die in our bodies every day typically don’t cause any problems because other cells swallow and digest their remains.  With her grant from the Lupus Research Alliance, Barbara Vilen, PhD, of the University of North Carolina at Chapel Hill found that this cleanup operation may fail in lupus because cells can’t break down their meals.

Pieces of dead cells end up in a structure called the lysosome, the cell’s version of a stomach.  Like our stomachs, lysosomes contain acid that helps dissolve their contents.  Dr. Vilen and colleagues determined that in mice that are prone to lupus, lysosomes don’t mature and so don’t produce enough acid. As a result, any cellular fragments a cell has swallowed will sit in the lysosome like a heavy lunch. Eventually the cell spits up this material, which ends up sticking to the cell’s surface. These undigested shards of cell corpses may trigger the immune system attacks of lupus.

By analyzing blood samples from lupus patients, the scientists found similar undigested cellular remnants that might also influence whether the disease is active. Patients with active disease were more likely to carry certain cell fragments on the surface of their immune cells than were patients whose disease was inactive. “We have identified a previously unappreciated cell biology defect that affects immune regulation,” says Dr. Vilen. Targeting the defect that prevents lysosomes from maturing might bring the immune system back under control, she says.

Kidney Genes Out of Sync
Many of our body functions, including our blood pressure and our sleep patterns follow a 24-hour cycle. Our kidneys also show a daily rhythm, working harder in the daylight hours than at night.  With her grant, Anne Davidson, MBBS, of the Feinstein Institute for Medical Research in Manhasset, New York, and her colleagues studied mice that develop lupus nephritis, or kidney inflammation, and found that genes that set these rhythms have bad timing.

The researchers measured the activity of genes in young mice whose kidneys were still healthy and in older animals that had kidney damage. In the young mice, key genes that help set the kidney’s clock followed the correct daily pattern. In the older mice, however, the genes worked hardest at the wrong time of day.  These altered rhythms could worsen kidney inflammation, the researchers suggest. Because the kidneys are important for breaking down drugs, they could also affect how patients respond to treatments.

High Salt in Tissues of Lupus Patients
Recent studies of animals have suggested that salt promotes autoimmune diseases—the group of illnesses, such as lupus and rheumatoid arthritis, in which the immune system mistakenly attacks patients’ own tissues. But whether salt plays a role in lupus remains unclear.  Michael Stein, MBChB, of Vanderbilt University Medical Center in Nashville and colleagues used their grant to confirm that lupus patients have higher levels of sodium in their muscles and skin than do people who don’t have the disease. Next step will be to see if extra salt boosts the numbers of certain immune cells that trigger inflammation.

Targeting Renegade Immune cells
The immune system cells known as B cells turn traitor in lupus, pumping out proteins that attack patients’ own DNA, RNA, and proteins that bind to these components.  Lupus Research Alliance funded work by Hui-Chen Hsu, PhD, of the University of Alabama at Birmingham and colleagues suggest a possible way to tame rogue B cells.

Before they can unleash an attack, B cells must mature. A molecule known as interferon-β helps the cells grow up and remain alive. The researchers found that maturing B cells from lupus patients produced more interferon-β than did cells from patients who didn’t have the disease. When the researchers blocked interferon-β, more B cells died before they could mature. Dr. Hsu and colleagues suggest that drugs that thwart interferon-β could help treat lupus, particularly after B-cell depletion therapy when B cells are repopulating from the bone marrow.  In a mouse study, Dr. Hsu and colleagues showed that such blockade promoted prolonged beneficial outcomes.


Promising Results Funded by Lupus Research Alliance Presented at American College of Rheumatology Annual Meeting

November 17, 2016

Modifying current malaria treatments to improve lupus treatment… Cells with indigestion may be key culprits … These are just two of the exciting results researchers funded by the Lupus Research Alliance presented this week at the American College of Rheumatology annual meeting in Washington, D.C.

Making New Drugs from Old
Malaria is caused by microscopic parasites that bore into our blood cells, so it might seem to have little in common with lupus. But despite many side effects, antimalarial drugs such as Plaquenil and Mepacrine have long been standard treatments for the disease. Keith Elkon, MD, of the University of Washington in Seattle and his colleagues believed they can improve these drugs.

Funded by the Lupus Research Alliance, the team used computer analysis and experiments on cells to gauge the effectiveness of several antimalarial compounds, including Plaquenil and Mepacrine . Lupus patients’ immune systems mistakenly attack their own DNA, and the researchers tested the drugs’ ability to block a cellular alarm system that misidentifies the DNA as a threat. The team then tweaked the drugs to improve their performance. One of the upgraded compounds, X6, was powerful but less toxic and showed promising results in ‘proof of principle’ therapy  in mice. “New antimalarial drugs that could be more effective than Plaquenil may be on the horizon,” says Elkon.

Cell Corpses Get Stuck in the Craw
The billions of cells that die in our bodies every day typically don’t cause any problems because other cells swallow and digest their remains.  With her grant from the Lupus Research Alliance, Barbara Vilen, PhD, of the University of North Carolina at Chapel Hill found that this cleanup operation may fail in lupus because cells can’t break down their meals.

Pieces of dead cells end up in a structure called the lysosome, the cell’s version of a stomach.  Like our stomachs, lysosomes contain acid that helps dissolve their contents.  Dr. Vilen and colleagues determined that in mice that are prone to lupus, lysosomes don’t mature and so don’t produce enough acid. As a result, any cellular fragments a cell has swallowed will sit in the lysosome like a heavy lunch. Eventually the cell spits up this material, which ends up sticking to the cell’s surface. These undigested shards of cell corpses may trigger the immune system attacks of lupus.

By analyzing blood samples from lupus patients, the scientists found similar undigested cellular remnants that might also influence whether the disease is active. Patients with active disease were more likely to carry certain cell fragments on the surface of their immune cells than were patients whose disease was inactive. “We have identified a previously unappreciated cell biology defect that affects immune regulation,” says Dr. Vilen. Targeting the defect that prevents lysosomes from maturing might bring the immune system back under control, she says.

Kidney Genes Out of Sync
Many of our body functions, including our blood pressure and our sleep patterns follow a 24-hour cycle. Our kidneys also show a daily rhythm, working harder in the daylight hours than at night.  With her grant, Anne Davidson, MBBS, of the Feinstein Institute for Medical Research in Manhasset, New York, and her colleagues studied mice that develop lupus nephritis, or kidney inflammation, and found that genes that set these rhythms have bad timing.

The researchers measured the activity of genes in young mice whose kidneys were still healthy and in older animals that had kidney damage. In the young mice, key genes that help set the kidney’s clock followed the correct daily pattern. In the older mice, however, the genes worked hardest at the wrong time of day.  These altered rhythms could worsen kidney inflammation, the researchers suggest. Because the kidneys are important for breaking down drugs, they could also affect how patients respond to treatments.

High Salt in Tissues of Lupus Patients
Recent studies of animals have suggested that salt promotes autoimmune diseases—the group of illnesses, such as lupus and rheumatoid arthritis, in which the immune system mistakenly attacks patients’ own tissues. But whether salt plays a role in lupus remains unclear.  Michael Stein, MBChB, of Vanderbilt University Medical Center in Nashville and colleagues used their grant to confirm that lupus patients have higher levels of sodium in their muscles and skin than do people who don’t have the disease. Next step will be to see if extra salt boosts the numbers of certain immune cells that trigger inflammation.

Targeting Renegade Immune cells
The immune system cells known as B cells turn traitor in lupus, pumping out proteins that attack patients’ own DNA, RNA, and proteins that bind to these components.  Lupus Research Alliance funded work by Hui-Chen Hsu, PhD, of the University of Alabama at Birmingham and colleagues suggest a possible way to tame rogue B cells.

Before they can unleash an attack, B cells must mature. A molecule known as interferon-β helps the cells grow up and remain alive. The researchers found that maturing B cells from lupus patients produced more interferon-β than did cells from patients who didn’t have the disease. When the researchers blocked interferon-β, more B cells died before they could mature. Dr. Hsu and colleagues suggest that drugs that thwart interferon-β could help treat lupus, particularly after B-cell depletion therapy when B cells are repopulating from the bone marrow.  In a mouse study, Dr. Hsu and colleagues showed that such blockade promoted prolonged beneficial outcomes.



1.5 million

people in the U.S. have Lupus.

172 million

dollars committed to lupus research by the Lupus Research Alliance.


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