World Kidney Day: Trinity researchers investigate rare autoimmune disease, AAV
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 Anti-Neutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (AAV), also known as small vessel vasculitis. There are two types of small vessel vasculitis: Wegeners’ Granulomatosis (GPA) and Microcropic 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, researchers 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 area also found in other disease conditions such as COVID-19, cancer and sepsis, but remain poorly defined. To coincide with World Kidney Day, we spoke to Irish Research Council-funded PhD researcher Amrita Dwivedi from the Trinity Health Kidney Centre who is working to understand the possible role of these low-density neutrophils in AAV pathogenesis. Amrita is supervised by Professor/Consultant of Nephrology, Professor Mark Little of the Trinity Health Kidney Centre and Dr Ronan Desmond, Consultant Haematologist at Tallaght University Hospital.
What is the title of your PhD and what is your background?
The title of my thesis is ‘cross-disease assessment of granulocyte phenotypic and functional heterogeneity’. I completed my BSc in Biological Sciences in Christ University in India where I majored in biotechnology, chemistry and zoology. I then obtained an MSc in Immunology in Trinity College Dublin where I undertook a research project in the lab of Professor Cliona O’Farrelly. Before starting my PhD, I worked as a Research Assistant for a year in Professor Mark Little’s lab.
How does your work directly impact health?
The aim of my research is to understand the role played by low-density neutrophils in the immunopathology of AAV, and how their role differs in other inflammatory diseases (such as COVID-19, cancer and sepsis). We have found that low-density neutrophils are aberrantly activated in AAV patients. These neutrophils actively produce the proteins that are targeted by ANCA antibodies and have been shown to readily damage the small vessels - suggesting that low-density neutrophils may play a key role in kidney and lung damage. I hope that my findings will broaden our understanding of the immunopathogenesis of AAV and will inform future studies which aim to identify potential therapeutic targets in patients with AAV. I believe that basic scientific research is the foundation of any medical advancement.
Did you always want to pursue this type of career?
My high-school biology teacher played a big part in nudging me on this career path. Growing up in India, engineering and medicine were the two main career options that most of my peers opted for but I wasn’t interested in either. My family hails from a small village in one of the most backward states in India where illiteracy is still prevalent. Despite the challenges, my uncle went on to become a biomedical scientist, studying at some of the most prestigious universities in India and USA. I was really inspired by his journey. I already had a keen interest in biological sciences and my undergraduate training provided a strong foundation for my further studies. I was particularly interested in learning about the immune system and the underlying mechanisms behind human diseases which led me to pursue a masters in immunology. During my masters, I was introduced to diverse topics in the field of immunology by researchers at the forefront of cutting-edge research. My decision to pursue a research career solidified after I finished my masters research project under the supervision of Dr Mark Robinson and Professor Cliona O’Farrelly. I enjoyed working in a research lab environment and the creative freedom it offered.
What do you enjoy most about your studies?
My favourite part about my studies is performing experiments in the lab. I enjoy the entire process of designing an experiment to analysing the results. It’s an absolute joy when your experiments work, but I have learnt lot more when my experiments failed. I truly believe that all the failed experiments have made me a better scientist. My studies have offered me the opportunity to learn new things as well as learn them at my own pace. I have been fortunate to work with some great colleagues who have been very supportive and encouraging throughout my PhD journey.
Carrying out academic research comes with its own challenges; it requires a lot of self-motivation and problem-solving. But if you are genuinely interested in your research area, it doesn’t feel like an insurmountable task. Undertaking a PhD is certainly not for everyone, it is an unusual path where you are trying to become an expert in a very niche area. My advice to undergraduates looking to do PhD would be to get some prior research experience in a lab to see if it suits you.
To learn more about the Trinity Health Kidney Centre, visit: https://www.tcd.ie/medicine/thkc/
To hear more about World Kidney Day, click here