Genetic and cellular basis of human immunological disease

Our laboratory operates within the Centre for Personalised Immunology. We operate at the interface between contemporary clinical practice and discovery, with overarching aims of improving diagnostic accuracy and devising more precise treatments through better understanding of disease mechanisms.

Characterising human genetic variation is a potentially powerful method for discovering mechanisms of disease. In some cases, a diagnosis of Mendelian disease can be made through WGS, and therefore we have implemented a diagnostic genomics service (Canberra Clinical Genomics). In other cases, whole genome sequencing identifies genetic variants that provide clues to mechanisms of disease. Our lab investigates the functional consequences of genetic variants using biochemistry and cellular immunology. In order to understand how genetically encoded changes in immunity cause pathology, we also develop bespoke models of human disease by engineering orthologous gene variants in mouse models using CRISPR/cas9. We have been applying this approach to many different types of immunological disease, but particularly primary antibody deficiency, autoimmunity and sarcoidosis.

Matthew Cook is Professor of Medicine at Australian National University (ANU), Director of Immunology at Canberra Hospital and Co-Director of the Centre for Personalised Immunology. He is also medical director of Canberra Clinical Genomics, which is a NATA-accredited diagnostic genomics facility, established as a joint venture between ACT Health and ANU. He is a clinician-scientist with more than 20 years of experience using genetic analysis to elucidate disease pathways, focussing on autoimmune and immune deficiency diseases. He has been chief investigator on numerous NHMRC project grants and three NHMRC program grants. He was elected as a foundation fellow of the RCPA Faculty of Science.

How do genetic variants affecting NF-kB cause autoimmunity and immune deficiency? 

In this project we are investigating several rare Mendelian disorders of NF-kB to understand how defects in these transcription factors alter central T cell tolerance, T and B cell development, and normal immune responses to infection.

AUTOCheck: immune related adverse events from checkpoint inhibitors 

Immune checkpoint inhibitors have transformed the management of many forms of cancer but sometimes treatment is complicated by development of organ-specific autoimmune diseases. In this study, we are investigating the genetic and cellular basis for susceptibility to these side effects. Insights gained from this study will help refine use of checkpoint inhibitors and potentially advance understanding of autoimmune disease.

Genetic and cellular basis of antibody deficiency

A large discovery program that aims to identify new causes of primary antibody deficiency (including CVID) beginning with WGS but encompassing functional analysis in model organisms to prove causation.

Australian Genomics Health Alliance Genetic Immunology rare disease flagship

AGHA aims to improve the implementation of genomics into routine clinical practice. The GI rare disease flagship is a national collaboration of scientists and clinicians working to improve diagnosis of patients with early onset autoimmunity. Immune deficiency and autoinflammatory diseases.

Mechanisms of sarcoidosis

Sarcoidosis is a chronic inflammatory disorder but curiously overlaps with immune deficiency. Sarcoidosis patients often exhibit low white cell counts and defective immune responses, but also experience inflammatory complications that sometimes lead to organ damage. The cause of sarcoidosis remans obscure and we are tackling this problem using genomics and cellular analysis.

Our Health in Our Hands (OHIOH) ANU Grand Challenge

OHIOH was funded as the inaugural ANU Grand challenge and is a collaboration between biomedicine, engineering, physics and computer science that is tackling the challenges of deep personalisation of medicine through genomics, wearables, nanodiagnostics and machine learning.

Projects are available in all research projects. If you are interested in joining the lab, please contact me by email.

• Investigating the role of NOD2 variants in auto-inflammatory diseases.
• Analysis of a novel heterozygous missense mutation in IKBKB.
• Investigation of molecular and cellular determinants of immune related adverse events following treatment with immune checkpoint inhibitors.
• CTLA4 deficiency with autoimmunity and immunodeficiency together in human.
• The Role of NFKB2 in B cell development and activation

• Characterisation of a novel mutation in IKBKB implicated in a primary immunodeficiency disease.
• Regulation of T cell differentiation by CTLA4 .
• Investigation of a novel mutation in IL21R implicated in a primary immunodeficiency disorder.
• Regulation of immune tolerance and autoimmunity by NFKB2.
• Investigation of genetic mechanisms of sarcoidosis