Grant: CIHR Fellowship

Bullous pemphigoid - Skin blisters occur when layers of the skin separate and body fluid collects in a pocket formed between the skin layers. While most of us have had blisters caused by friction, sunburns, or infections, some patients suffer from conditions that cause the blisters spontaneously all over the body. Bullous pemphigoid (BP) is the most common blistering disease and often affects the elderly. As our skin forms an important barrier to protect against infection, loss of moisture, temperature changes, and other factors, widespread blisters in BP interrupt these functions and can be life-threatening. Unfortunately, there are currently limited treatment options for BP. Standard treatment with oral corticosteroids is not effective for all patients and can lead to serious side effects, especially in the elderly. Therefore, there is an urgent need to better understand the disease to develop more effective treatments. The role of granzyme B in BP - In healthy people, the immune system produces proteins called antibodies that help fight foreign entities such as bacteria and viruses. In BP patients, the antibodies mistakenly attack the body's own proteins - specifically, anchoring proteins which attach top skin layers to the deeper layers. When antibodies recruit immune cells for the attack, they release "molecular scissors" called proteases that cut proteins. Our laboratory has discovered a protease called granzyme B that is elevated in the skin of BP patients and appears to induce blistering by cutting the anchoring proteins that hold the skin layers together. Based on these findings, I propose that granzyme B contributes to the onset and severity of BP. I will investigate the role of granzyme B in BP using skin cells, animal models, and human patient samples and test the therapeutic efficacy of a granzyme B inhibiting drug in the animal models. Results from this work will support the development of this inhibitor into a treatment for BP and other diseases.