Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

Inborn errors of immunity (IEI) are rare genetic disorders in which mutations lead to components of the human immune system being absent or dysfunctional. My research focuses on two recently discovered IEIs. 1) MSN codes for a protein that allows a type of white blood cell called lymphocytes to multiply and activate immune pathways that defend the body. We have identified four boys with the same MSN mutation who developed severe rashes, recurrent infections, low lymphocyte levels, and lung complications (two of the boys have passed away from this disease). This project will investigate how this mutation affects the amount and function of the protein encoded by MSN. Then, using genetic engineering, I will introduce a normal copy of the MSN gene into patients' lymphocytes, and monitor whether the lymphocytes regain the ability to multiply and function properly. 2) STAT6 allows many types of white blood cells to survive, multiply, and differentiate into specialized types of immune cells. If this gene is overactive, patients develop severe allergic disease, such as eczema, allergic asthma, food allergies, and gastrointestinal complications. We have identified 12 mutations that lead to an overactive STAT6 protein in patients. This project will investigate how these mutations alter healthy functions to drive disease in patients' white blood cells and in genetically engineered cells (in which I create the overactive STAT6 mutations). Finally, I test whether a drug developed to treat patients with overactive STAT6 mutations can restore function in these patients' cells. This research will enhance our understanding of two IEIs and aid in the diagnosis and treatment of affected patients. If we confirm the MSN mutation causes disease, the mutation can be added to tests used to diagnose IEIs, and patients will become eligible for treatment. Our studies of STAT6 disease will not only help treat our patients but also provide insight into common forms of allergic disease.