Identification Of Antigen Selection In The Human IgE Response By Analysis Of Somatic Point Mutations
Funder
National Health and Medical Research Council
Funding Amount
$256,973.00
Summary
Allergic disease affects over 25% of the Australian community. It is responsible for significant sickness and death, particularly amongst children, and its incidence is on the increase. The reasons for this, and the underlying causes of allergic disease, remain unclear. Allergic disease results from the actions of molecules called IgE antibodies, which are also associated with parasitic infection. Even in these conditions, where IgE concentrations are raised in the blood, the concentrations are ....Allergic disease affects over 25% of the Australian community. It is responsible for significant sickness and death, particularly amongst children, and its incidence is on the increase. The reasons for this, and the underlying causes of allergic disease, remain unclear. Allergic disease results from the actions of molecules called IgE antibodies, which are also associated with parasitic infection. Even in these conditions, where IgE concentrations are raised in the blood, the concentrations are too low to allow their direct study. We have recently applied molecular biological techniques to study the genes that encode IgE antibodies. Our work suggests that the IgE response can sometimes develop in a different way to that of other antibodies (eg IgG). On the other hand, laboratory (in vitro) studies over many years support the possibility that IgE and IgG develop in parallel. In this study, we wish to identify circumstances in which IgG-like IgE antibodies develop. We therefore wish to study patients with different kinds of allergic disease, and patients with other conditions that are associated with IgE production. We therefore wish to study patients who have infections with parasitic worms. We deduce the processes that give rise to IgE antibodies by analysing patterns of mutations that accumulate in antibody genes during an immune response. Over recent years, we have developed new approaches to the analysis of such mutations, and this project also seeks to further develop our mutation analysis. This more powerful analysis will be applied to the study of mutations in the IgE genes seen in different patient groups, and should allow us to quantify the proportion of IgE antibodies that develop in each way. A better understanding of the relative contributions of the two pathways to IgE, in different conditions, will transform our understanding of the IgE response, and open up new avenues for the investigation of the causes and treatment of allergic disease.Read moreRead less
DETERMINING THE ROLE OF ER STRESS INDUCED APOPTOSIS IN THYMIC NEGATIVE SELECTION
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
Apoptosis is an evolutionarily conserved mechanism for killing unwanted cells that are no longer needed, damaged, infected with pathogens or dangerous. Defects in apoptosis can cause a number of diseases. For example, abnormal survival of cells can cause cancer or autoimmune disease. Bim is a protein that induces apoptosis and act as a barrier against cancer and autoimmune diseases. This work is aimed at understanding how Bim acts as a barrier against the development of autoimmunity.
The Molecular Basis Of HLA-linked Drug Hypersensivity Reactions
Funder
National Health and Medical Research Council
Funding Amount
$683,040.00
Summary
Adverse drug reactions are one of the leading causes of death in hospitalised patients. We have discovered a new mechanism that links these reactions to recognition of drug induced changes in immunological self, resulting from interactions of drugs with immune receptors. This project probes the generality of this mechanism by examining the basis of life threatening reactions to drugs used to treat epilepsy (carbamazepine), gout (allopurinol), HIV (Nevirapine) and towards aspirin a commonly used ....Adverse drug reactions are one of the leading causes of death in hospitalised patients. We have discovered a new mechanism that links these reactions to recognition of drug induced changes in immunological self, resulting from interactions of drugs with immune receptors. This project probes the generality of this mechanism by examining the basis of life threatening reactions to drugs used to treat epilepsy (carbamazepine), gout (allopurinol), HIV (Nevirapine) and towards aspirin a commonly used pharmaceutical.Read moreRead less
Understanding The Complexity Of Antigen Presentation
Funder
National Health and Medical Research Council
Funding Amount
$774,540.00
Summary
I have developed and established the use of mass spectrometry to identify and quantitate ligands of antigen presenting molecules to understand the breadth of immune responses in a variety of human disease states including autoimmunity, cancer, infection and allergy. By embedding the technology in disease focussed research programs I will define the molecular bases of these diseases and the important immunological targets that will provide new avenues for therapeutic development and vaccines.
Investigation Of Small Molecule Interactions With The Human Leukocyte Antigen And Their Role In Non-infectious Disease
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
The Human Leukocyte Antigens (HLA) play a key role in the immune system helping the body differentiate healthy from diseased cells. Numerous autoimmune diseases and adverse drug reactions are associated with specific HLA variants. This study seeks to unlock the mechanisms behind these diseases, investigating how small molecules including drugs interact with the HLA to make healthy body cells seem foreign. This research has the potential to inform strategies for disease avoidance and management.
Antigen Presentation During HLA B27 Associated Auotimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$715,365.00
Summary
Ankylosing spondylitis is a debilitating arthritic disease, susceptibility to which is conferred by genes of the immune system, particularly HLA-B27, and following gastrointestinal infection. Using mass spectrometry we will identify bacterial peptides bound to HLA-B27 on infected cells that may trigger an autoimmune response. Defining the self peptides that remain the targets of autoimmunity will unravel the molecular and cellular mechanisms if disease and identify peptides for immunotherapy.
The Molecular Basis Of HLA-linked Drug Hypersensitivity
Funder
National Health and Medical Research Council
Funding Amount
$827,536.00
Summary
Adverse drug reactions are one of the leading causes of death in hospitalised patients. We discovered a new mechanism that links these reactions to recognition of drug induced changes in immunological self, resulting from interactions of drugs with immune receptors. This project continues to probe the mechanisms of immune mediated drug reactions by examining the basis of life threatening reactions to drugs used to treat epilepsy, gout and commonly used drugs such as penicillin and aspirin.