Autoimmune diseases such as lupus are on the rise, affecting people worldwide and draining healthcare resources. The causes are complex and multifactorial; both genetic and environmental factors are involved. Primary immune deficiencies (PID) are monogenic defects of our immune system. Not only do PID patients suffer from recurrent infections, up to 1 in 4 patients develop autoimmunity or hyperinflammation. As such, PIDs are an ideal model to better understand autoimmune diseases. Recently, we identified a new mutation in the RC3H1 gene in a PID patient suffering from hyperinflammation. The importance of RC3H1 in the immune system is already shown in mice; mice carrying mutations in RC3H1 develop lupus-like immune disease. In collaboration with Prof Vinuesa and Prof Heissmeyer, two expert scientists in RC3H1 biology, we established the causal link between the RC3H1 mutation and the immune disease of the patient.
In this project, we set out to understand the role of RC3H1 and its family member ZC3H12A in immune disease. In collaboration with the Australian National University, we identified a number of damaging mutations in RC3H1 and ZC3H12A in patients with lupus or PID with autoimmunity or hyperinflammation. Combining our established tools with high-throughput innovative technology, we aim to functionally test these mutations and comprehend how they result in disease. This understanding may alter our views on immune regulation and provide better therapeutical approaches.