Dr Alison Condliffe

My research focuses on the role of neutrophil and eosinophil granulocytes as mediators of tissue injury in respiratory disease. I have a particular interest in the phenomenon of neutrophil priming, which increases potential of these cells to cause tissue injury and disease. My group also studies the effects of hypoxia (low oxygen levels) on granulocyte function, the mechanisms of glucocorticoid resistance in asthma, and the distribution and fate of eosinophils in health and in allergic disease as determined by novel imaging methodologies. One of my main clinical interests is the respiratory problems in primary immune deficiency, and this has led to a further major research initiative.

Both inflammatory cytokines such as GM-CSF, LPS, and TNFα, and also hypoxia, can lead to neutrophil priming. Primed neutrophils release approximately tenfold more reactive oxygen species and proteolytic enzymes such as neutrophil elastase when stimulated than do unprimed cells. We have shown that lipid second messengers generated by the phosphoinositide 3-hydroxykinase (PI3K) signaling system are critical in signaling the enhanced responses seen in primed cells, and in prolonging granulocyte lifespan in response to cytokines.

In collaboration with Dr Sergey Nejentsev (Department of Medicine), Dr Roger Williams (LMB), the Clinical Immunology Service (Addenbrooke’s Hospital), and with scientists at the Babraham Institute, I have identified and characterized a novel and severe immune deficiency syndrome termed ‘Activated PI3kinase delta Syndrome’ or APDS, that is caused by a a newly described autosomal dominant mutation in the gene coding for the catalytic subunit of PI3K delta. This mutation leads to increased constitutive and stimulated activity of this key signaling enzyme, and we are currently investigating precisely how this results in the very profound susceptibility to bacterial and viral infection that we see in the patients.

Ongoing projects in the laboratory include the effects of hypoxia on granulocyte signaling pathways, the role of hypoxia in glucocorticoid resistance, and the role of the PI3K pathway in immune dysfunction both in general, and in APDS in particular.