It is feasible to sequence patient genomes but we need to know more about how genetic variants cause complex disease. We have sequenced genomes from patients with immune deficiency and will test the idea that genetic variation causes consistent changes in particular white blood cells, thus providing a bridge between genomic information and clinical diagnosis. Outcomes will include more accurate diagnosis, better understanding of immunity, and a strategy for using whole genome information.
Determining The Unique Processes That Control Memory B Cell-mediated Secondary Antibody Responses
Funder
National Health and Medical Research Council
Funding Amount
$853,644.00
Summary
Vaccines educate the immune system by training memory cells to make neutralizing antibodies when it re-encounters the pathogen. However, where and how these memory cells are activated in the secondary antibody response in immune animals remain unknown. Here we use cutting edge technologies to fate map and gene profile memory cells and determine the molecular switches that control the secondary antibody response. This will be complemented by human vaccine studies.
Investigating B Cell Development, Maintenance And High-affinity Antibody Production By ENU Mutagenesis
Funder
National Health and Medical Research Council
Funding Amount
$408,388.00
Summary
B cells are essential for the protection against infections. This application aims to identify new genes that are crucial for the development or function of B cells and will investigate how mutations in newly discovered genes contribute to defects in the development and function of B cells and the pathogenesis of B cell leukaemia.
Novel Posttranscriptional Pathways The Control Tfh Cell Numbers
Funder
National Health and Medical Research Council
Funding Amount
$647,539.00
Summary
T follicular helper (Tfh) cells are essential for effective antibody responses against infection. Limiting Tfh cells is crucial for selecting the "fittest" B cells and the success of vaccines. Tfh cell accumulation causes autoimmuity and is associated with inadequate B cell responses in HIV infection. We have recently discovered two novel pathways that control Tfh cells. We speculate they regulate different RNAs that influence Tfh homeostasis and aim to elucidate their mechanism of action.
Germinal Centres, Rogue B Cells And The Genesis Of Immunological Diseases.
Funder
National Health and Medical Research Council
Funding Amount
$753,300.00
Summary
This study will determine how the immune system is normally prevented from producing autoantibodies that target the body's own cells and how this fails in autoimmune diseases such as lupus. Targeted studies of a newly discovered "rogue" white blood cell will also provide new clues on how autoimmune diseases arise. In addition, modeling of human immunological disease in mice via CRISPR/Cas9 mutagenesis will provide valuable new insights into their causes and potential treatments.
In this project, we will determine how a protein called ACKR4 suppresses antibody production and determine whether inhibiting its function will enhance the effectiveness of vaccination.
Understanding the immune response is proving extremely complex and promising results for disease treatments from animal models are often difficult to translate to new clinical therapies. My research is unearthing weaknesses in our current knowledge of the immune system and seeking to replace them with a foundation that can exploit new developments in computer modelling and systems biology. In this way I aim to rationally manipulate the immune response.
T-follicular Helper Cell Subtypes That Induce Protective Anti-malaria Antibodies
Funder
National Health and Medical Research Council
Funding Amount
$431,000.00
Summary
Malaria causes significant disease burden globally. Currently there are no malarial vaccines that are suitable for widespread use. The development of effective vaccines is hampered by limited understanding of how the human immune system fights malaria. This project will use human samples collected to investigate how human blood cells activate the immune system to fight malaria. This research will identify avenues to improve the design of malaria vaccines in the future.
Positive And Negative Selection In The Germinal Centre Reaction
Funder
National Health and Medical Research Council
Funding Amount
$1,289,965.00
Summary
We will investigate the processes that control the production of antibodies by the immune system. In particular, we will determine how the immune system is normally prevented from producing autoantibodies that target the body's own cells and how this fails in the case of autoimmune diseases such as lupus. Targeted studies of a new type of "rogue" white blood cell we have identified will also provide important clues on how autoantibody-producing cells escape and cause autoimmune disease.