Discipline: Clinical Medicine - Nephrology

Cross-Disease Assessment of Phenotypic and Functional Granulocyte Heterogeneity

PhD Student: Amrita Dwivedi Supervisor: Professor Mark Little Funding: Irish Research Council

Overview of Project: Neutrophils are the most abundant immune cells in our body and play an important role in defence against infections and other threats. Defects in neutrophil function can have severe consequences and lead to various diseases. One such disease is AntiNeutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV), also known as small vessel vasculitis. There are two types of small vessel vasculitis: Wegener’s Granulomatosis (GPA) and Microscopic polyangiitis (MPA). Both types are characterised by antibodies that target the body’s own neutrophil proteins causing defective neutrophil function. AAV is a rare disease, but can result in organ damage and failure, with the kidney and lung as major targets. As many as a quarter of AAV patients who require renal replacement therapy (kidney dialysis) at the time of diagnosis die within six months of diagnosis, and one in three patients never regain kidney function. Neutrophils were traditionally thought to be a uniform cell type with a well-defined role in the immune system, however, it is now thought that neutrophils are made up of several subclasses with specialised function which either resolve or worsen inflammation. Researchers at The Trinity Health Kidney Centre, based in the Trinity Translational Medicine Institute in Trinity College Dublin have previously shown that, in addition to normal neutrophils, a subclass of neutrophils (called ‘low density granulocytes/ neutrophils’) is increased in patients with AAV and is related to how severe the disease is. However, they do yet not understand whether these low-density neutrophils are directly causing AAV or whether they increase in response to inflammation. Interestingly, these low-density neutrophils are also found in other disease conditions such as COVID-19, cancer and sepsis, but remain poorly defined.

Long-term impact of Project: These findings will broaden our understanding of the immunopathogenesis of AAV and will inform future studies that aim to identify potential therapeutic targets in patients with AAV.

Quote: “I believe that basic scientific research is the foundation of any medical advancement.”