Published in Nature Communications, the scientists created a new animal model of disease to determine if BBB leakage can cause autoimmunity. They discovered that injecting just one drop of blood into the brain set off the brain's immune response, kick-starting a chain reaction that resulted in inflammation and myelin damage.
Myelin is the protective sheath that insulates nerve fibers in the brain, and it is the primary site of injury in MS. What's more, the scientists were able to pinpoint a specific protein in the blood, the blood-clotting factor fibrinogen, as the trigger for the disease-causing process.
Fibrinogen activated the brain's immune cells, called microglia, and caused them to send out signals summoning peripheral immune cells from other parts of the body to the brain. When these peripheral immune cells—macrophages and T cells—entered the brain, they attacked myelin.
To confirm their findings, the scientists deleted the fibrinogen receptor (complement receptor 3 or CD11b/CD18) on microglia, thereby preventing fibrinogen from activating the cells. Inhibiting this interaction blocked the autoimmune process, stopping the microglia from signaling to the peripheral immune cells and averting myelin damage and inflammation.
The researchers are now attempting to block fibrinogen using biological and small-molecule approaches as potential new therapies to suppress autoimmunity directed against the brain, dampening inflammation caused by microglia and T cells.
The scientists say that having a model of blood-induced brain inflammation is a valuable tool, as it can be used to screen new drugs. These mechanisms may occur not only in autoimmune disorders, but also in other brain diseases that involve inflammation or a break in the BBB, including traumatic brain injury, stroke, Alzheimer's disease, and other dementias.