Grant: Operating Grant - PA: Genetics (Bridge Funding: Research Priorities)

Our immune system protects us from infections, controls inflammation, and prevents allergies and autoimmunity. When single mistakes (variants) occur in important immune genes, people can develop inborn errors of immunity (IEIs)-rare but serious conditions that cause repeated infections, severe allergies, autoimmunity, or cancer. More than 500 IEIs have been discovered, yet many people with life-threatening immune problems still do not receive a diagnosis. Without answers, patients and families face uncertainty, delayed care, and limited options. Our team of doctors and scientists has recently discovered three new IEIs caused by rare changes in the genes MYB, SIGLEC8, and MALT1. These disorders lead to dangerous immune imbalance from early in life which can be fatal. Studying these newly discovered IEIs offers a window into how the immune system works and provides opportunities to develop targeted treatments that can improve health. In this project, we will: -Use state-of-the-art genetic and cellular tools to confirm how these gene changes disrupt immune cells. -Study patients' blood cells and compare them to healthy controls to understand how their immune systems fail. -Build "disease-in-a-dish" models using cells and gene engineering to test how the variants cause disease. -Search for existing medications that can be repurposed to correct these defects, bringing potential treatments faster. This research will directly benefit affected individuals by providing long-sought answers, accurate genetic diagnoses, and new opportunities for treatment. Results will be shared through international networks so that others worldwide can be tested and receive proper care. Beyond rare diseases, this work will also uncover immune pathways relevant to common conditions such as asthma, allergy, autoimmunity, and infection. In short, our project will transform lives by turning rare immune disorders into opportunities for discovery, diagnosis, and hope for precision therapies.