Utilizing inborn errors of immunity to review novel insights into atopic disease

 Supervisor: Prof Cindy Ma, Head, Human Immune Disorders Laboratory.

Allergy and atopic diseases are among the fastest growing chronic conditions in Australia, with 1 in 3 individuals affected by allergic disease and 1 in 10 infants experiencing food allergies. Furthermore, the incidence of severe allergies and the number of allergy-related hospitalizations has increased 4-fold in the last 20 years. In addition to representing major health issues in Australia, they impose a significant cost of $7.8 billion annually. The cellular basis of allergic disease involves distinct but co-operating immune cell types: pathogenic T helper 2 (Th2) lymphocytes, which aberrantly produce excessive amounts of the cytokines interleukin (IL) IL-4, IL-5 and IL-13, and activated B cells that produce pro-allergenic IgE antibodies. However, the pathways driving dysregulation of these lymphocyte populations are unknown. Thus, strategies are needed to enable better understanding of the pathogenesis of allergic and atopic disease, which can then be leveraged to develop novel treatments for these common conditions that dramatically impact quality of life.

Inborn errors of immunity (IEIs) are caused by germline mutations in single genes that affect the development and/or function of immune cells. IEIs are typically associated with increased susceptibility to severe, recurrent and often life-threatening opportunistic infections. However, the phenotypic spectrum of individual IEIs is very broad, and extends beyond infectious diseases to include autoimmunity, malignancy and - of particular significance to this project - allergy. In fact, severe allergic or atopic disease is a defining feature of ~40 of the 485 genes identified to cause IEIs, when mutated, result in early-onset and treatment-resistant eczema, life-threatening allergy, atopy, eosinophilia, and hyper-IgE syndromes. This project will leverage our unique access to these rare patients to study the roles of genes, molecules, signalling pathways and/or cell types in atopic disease. This will be achieved by state-of-the-art techniques such as multiparameter flow cytometry, and bulk and single cell RNA-seq. The end goal is to further our understanding of the mechanisms driving different types of atopic disease and to reveal better therapies for the treatment of these immunopathologies.