B cell dependent susceptibility to airway infection in Activated PI3K-delta syndrome (360G-Wellcome-206618_Z_17_Z)

PI3Kdelta plays a critical role in development of the immune system. We have identified a cohort of patients with an immunodeficiency caused by gain of function mutations in PI3Kdelta, which we have named Activated PI3Kdelta syndrome (APDS). My fellowship proposal will determine how dysfunctional B cells contribute towards recurrent pneumonia associated with APDS. I have shown that aberrant PI3Kdelta signalling leads to significant defects in B cell development and function. I have found that hyper-activated PI3K signalling in B cells alone is responsible for increased susceptibility to Streptococcus pneumoniae in a mouse model. Surprisingly, this defect appears to be antibody independent. I have discovered a subpopulation of IL10 producing B cells that I believe represents a new type of B cell with immune-regulatory properties. I hypothesise that this B cell subset is contributing to the immunopathology secondary to pneumococcal infections in APDS, leading to bronchiectasis. My aims are: To characterise this newly discovered subset of B cells and explore the role of PI3Kdelta in their ontogeny. To determine whether IL10 is the innate cytokine that triggers antigen non-specific activation and immunopathology. To explore whether these pathogenic cells can be manipulated therapeutically using oral or inhaled PI3Kdelta inhibitors.