October 1, 2020
In a recent Lupus Research Alliance supported study published in Frontiers in Immunology, Dr. Ziaur Rahman linked molecules called TLR7 and type II interferon to impairing the ability of immune cells to do their job. These findings support further development by several companies of lupus treatments that block TLR7 and type II interferon.
Inflammatory molecules like TLR7 and type II interferon contribute to the development of lupus. These molecules help immune cells like B cells to secrete proteins called autoantibodies that attack healthy human tissues. Normally, B cells attack invading microorganisms like bacteria and viruses. However, in lupus, some B cells may attack healthy cells if they see human genetic material (DNA and RNA) floating in the blood. Normally the genetic material is hidden inside healthy cells and cannot escape. But tissue damage and infections can cause cells to die and release DNA into the bloodstream. When B cells attack this genetic material, more healthy human cells are destroyed. As healthy cells are destroyed, more genetic material is released, so more B cells then can see them and attack. This cycle causes the number of B cells that attack the body to go up and can lead to autoimmunity.
However, specialized B cells known as regulatory B cells can stop this cycle. These cells “regulate” the immune response by reducing inflammation caused by other nearby B cells. When inflammation reduces, less genetic material is released and it is less likely for other B cells to attack healthy human cells.
Previous research suggested that inflammation causes the development of regulatory B cells. But the role of the inflammatory molecules TLR7 and type II interferon in this process was unclear. Therefore, Dr. Rahman and his team used a mouse model of lupus to explore if TLR7 and type II interferon help the immune system create more regulatory B cells. By genetically altering mouse B cells so that they no longer had the ability to recognize TLR7 or type II interferon, he could study if either molecule caused the development of regulatory B cells. Surprisingly, Dr. Rahman found that inflammation from TLR7 and type II interferon prevented regulatory B cell development instead of helping it. With less regulatory B cells, the immune system was less able to stop inflammation, causing the mice to develop lupus. But blocking TLR7 or type II interferon allowed regulatory B cells to develop and protect the mice from lupus.
Dr. Rahman’s findings suggest that increasing the number of regulatory B cells in a patient can lower the impact of B cells that target healthy human cells. These results highlight the potential benefit for drugs blocking TLR7 and type II interferon molecules in treating lupus in humans.
“The grant from the Lupus Research Alliance helped us identify the roles of two inflammatory molecules such as TLR7 and type II interferon in the development of lupus-promoting B cells,” explained Dr. Rahman. “The grant further helped us discover that these two molecules also prevent the development of B cells (called regulatory B cells) that protect us from the disease. Thus, targeting these two inflammatory molecules would help treat lupus patients.”
