Uncovering the functional and genomic defects driving Predominantly Antibody Deficiency

Inborn Errors of Immunity (IEIs) are caused by rare genetic variants. Despite of major advances in genetics, in many patients no rare causative variant is identified. This is most prominent in Predominantly Antibody Deficiency (PAD), the most prevalent IEI (62% of IEI cases in Australia) with 75% undiagnosed cases. As a consequence, patients experience lengthy diagnostic delays (up to 9 years) and miss out on effective therapy leading to irreversible organ damage and early death. However, current genomic approaches aimed at identification of single causative gene variants do not suffice. We believe that a subset of undiagnosed PAD patients carry two or more rare or common variants in separate genes that interact to cause disease. To address this, we will study the functionality of immune signalling pathways of human B cells, T cells and monocytes to diagnose pathway defects, and use this information to interrogate genes controlling these pathways to identify variants in genes controlling these pathways. We have access to human PBMC samples from PAD patients, and raw data from WES of these patients. Students will learn how to isolate PBMC, perform assays examining immune signalling function, culture human cell lines and use multicolour (spectral) flow cytometry. Resulting data will be analysed using FlowJo. A better understanding of the molecular and cellular defects of human immune cells in PAD, will ultimately lead to increased diagnosis and more effective treatment of PAD.