Zarafov, Antonios; (2018) Investigating functional and biochemical consequences of p110 delta overactivity in innate immunity. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Activated PI3Kδ syndrome (APDS) is a recently described primary immune deficiency characterised by gain-of-function (GoF) mutations in the PIK3CD gene which encodes the leukocyte-restricted p110δ catalytic subunit of phosphoinositide 3-kinase enzyme (PI3K) known to be important in cell survival, growth and migration. So far, defects of T and B-cell function have been reported but other immune cell types have not yet been well studied. Although p110δ is known to have a role in myeloid cells, the impact of APDS on innate immunity is currently unknown. Here, using both human APDS samples and a murine model of APDS, we demonstrate that the E1021K GoF mutation in p110δ is associated with enhanced PI3K signaling basally as well as upon TLR4 ligand lipopolysaccharide (LPS) stimulation in dendritic cells (DC). Surprisingly, no effect of the mutation was observed on cytoskeletal function. However, APDS DC displayed altered LPS signaling, resulting in impaired IL- 12 and IFN-β secretion. In a murine model of APDS, reduced IFN-β secretion by DC in turn led to diminished autocrine and paracrine IFN-β signaling, which culminated in defective production of anti-microbial nitric oxide. We hypothesise that this may contribute to increased susceptibility of APDS patients to bacterial infections, warranting further investigation.

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