Identifying The Underlying Mechanisms Responsible For The Generation Of Pathogenic B Cells In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$163,755.00
Summary
Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are r ....Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are responsible for most of the damage to the beta cells in T1D. Recent work in this model, however, has demonstrated that another class of immune cell, termed B cells, also play an important role in T1D as NOD mice made deficient in these cells no longer develop disease. In addition to producing antibodies, B cells are one of the few cell types which are able to take up and present protein fragments in a form recognizable to T cells. Normally, this only leads to the activation of T cells recognising foreign insults, like viruses or bacteria, resulting in their destruction. We have shown that a dangerous population of B cells can arise in NOD mice that can specifically take up beta cell proteins and present them to the T cells, which subsequently become armed to recognise and destroy the beta cells. Just like T cells, B cells that recognize the body's own proteins are normally eliminated in healthy mice and human individuals. This research proposal aims to determine the faulty immune mechanisms that give rise to the beta cell specific B cells in NOD mice. We have also set out to identify the diabetes susceptibility genes which control the generation of this dangerous population of B cells in this model. By understanding how these dangerous B cells are generated in NOD mice, we hope to form the basis for new therapies aimed at inhibiting these cells from forming in T1D susceptible humans, thus preventing the disease at an early stage.Read moreRead less
Antiphospholipid Antibodies, Beta 2-Glycoprotein I And Control Of Coagulation.
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
Antiphospholipid antibodies are associated with an autoimmune condition characterised by the presence of clots and recurrent miscarriages. Although the name implies that the antibodies bind phospholipid the disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2-Glycoprotein I. The exact role of Beta 2-GPI in the body has not been determined, although there are numerous studies looking at this protein. This protein has been thought to be important in ....Antiphospholipid antibodies are associated with an autoimmune condition characterised by the presence of clots and recurrent miscarriages. Although the name implies that the antibodies bind phospholipid the disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2-Glycoprotein I. The exact role of Beta 2-GPI in the body has not been determined, although there are numerous studies looking at this protein. This protein has been thought to be important in controlling the clotting system in humans and other mammals. The evidence for this has been contradictory, however, we have recently made a major new finding on the function of this protein on the clotting system. We will be using sophisticated molecular biology techniques to further characterise the role that Beta 2-GPI has in controlling clotting factors in the body. We have been able to eliminate the gene for Beta 2-GPI in mice thus deriving mice that do not produce any Beta 2-GPI protein. These mice are called Beta 2-GPI knockout mice and will be an ideal animal model to examine the function of Beta 2-GPI and its new role in controlling the clotting cascade by targetting a specific part of this pathway. In addition, these findings may be able to provide new information on how Beta 2-GPI controls clotting factors and the effect of antiphospholipid antibodies on this system, which may lead to new treatments for antiphospholipid antibodies and more generally clotting disorders.Read moreRead less
Immune Tolerance In Experimental Autoimmune Encephalomyelitis Following Transplant Of Bone Marrow Cells Genetically Encoding Autoantigen
Funder
National Health and Medical Research Council
Funding Amount
$339,143.00
Summary
Autoimmune diseases affect 5-6% of the population and include diseases such as multiple sclerosis. Our studies focus on examining a gene therapy approach together with bone marrow transplantation to treating autoimmune diseases. Using a model for multiple sclerosis we are finding promising results
Investigations In Multiple Sclerosis Patients With Coexistent Autoimmune Thyroid Disease
Funder
National Health and Medical Research Council
Funding Amount
$557,100.00
Summary
Multiple sclerosis (MS) is a common chronic neurological disease affecting over one million people around the world. MS is generally thought to be an autoimmune disease, in which a person's own immune cells start to attack components of the brain and spinal cord. However, it is thought that the same components are not attacked in all patients, and that the pathway that leads to MS varies from one person to another. Therefore, in order to develop successful treatment strategies for MS, it will be ....Multiple sclerosis (MS) is a common chronic neurological disease affecting over one million people around the world. MS is generally thought to be an autoimmune disease, in which a person's own immune cells start to attack components of the brain and spinal cord. However, it is thought that the same components are not attacked in all patients, and that the pathway that leads to MS varies from one person to another. Therefore, in order to develop successful treatment strategies for MS, it will be necessary to look for patterns in the clinical symptoms and signs and other features of a person's MS that may give clues as to which particular pathway is leading to disease in that person. Some people who develop MS also develop other autoimmune diseases, or have these other diseases before they develop MS, or have other family members who have other autoimmune diseases. We have recently found that people who have the same combination of coexistent MS and autoimmune thyroid disease (AITD) show similar clinical signs of MS, and tend to have damage (lesions) to the same areas of their nervous system. This suggests that these people may have the same underlying pathways leading to the development of MS, and that they may be a very informative group in which to look for immune or genetic abnormalities that might explain why they develop MS. This project will investigate people who have both MS and AITD and other members of their families to see if we can work out what the links are between having the same combination of autoimmune diseases and developing lesions in particular parts of the nervous system. It will provide information on the pathways that lead to the development of MS, and information obtained from this study may eventually be of use in developing more specific therapeutic agents, by tailoring therapies to specific people with MS, depending on the clinical and immunological profile of that person.Read moreRead less
Translational Study Of The Genetics Of Systemic Autoimmunity Based On Mouse Mutagenesis
Funder
National Health and Medical Research Council
Funding Amount
$518,500.00
Summary
Lupus is the prototypic autoimmune disease. It is characterised by inflammation that can damage virtually any organ in the body. This inflammation is the outcome of a complex interplay between the environment and genetic predisposition, resulting in production of antibodies against components of normal tissue. Better characterisation of the genetic basis of lupus is a priority because it is the single best path towards a clearer understanding of the mechanism of this debilitating disease, and ul ....Lupus is the prototypic autoimmune disease. It is characterised by inflammation that can damage virtually any organ in the body. This inflammation is the outcome of a complex interplay between the environment and genetic predisposition, resulting in production of antibodies against components of normal tissue. Better characterisation of the genetic basis of lupus is a priority because it is the single best path towards a clearer understanding of the mechanism of this debilitating disease, and ultimately, new therapeutic options. Strategies used to identify the genetic basis of human disease fall into two categories. The first involves gathering genetic information from families with more than one affected member, which is then compared with genetic information from unaffected people. This can identify genetic regions likely to contain disease-causing genes, but so far, this approach has met with limited success in lupus. Although regions of the genome that harbour disease-associated genes have been found, few actual disease causing genes have been confirmed. The second approach begins with known genes that might plausibly cause the disease, based on prior knowledge then tests are performed to see whether particular variants of these genes are more common in patients than in healthy controls. Obviously this approach is usually biased towards investigation of candidate genes that are already well-characterised. In this project, we will combine information obtained from a large-scale mouse-based programme in which genetic changes that cause features of lupus are generated randomly. In other words, there is an unbiased search for candidate genes, which should lead to the discovery of new disease pathways. Since the mouse and human immune systems are remarkably similar, genetic abnormalities that cause features of lupus in mice are highly likely to be informative about the genetic basis of human lupus, a hypothesis we will test with genetic studies in humans with lupus.Read moreRead less
The Role Of Interleukin (IL)-27 In The Germinal Centre Reaction During Normal And Autoimmune Responses
Funder
National Health and Medical Research Council
Funding Amount
$476,226.00
Summary
Protective immune responses depend on supportive interactions between different white blood cell types. Signalling proteins called _cytokines� are a key means of communication between cells. Abnormal cytokine production can lead to poor protection against infection or immune attack against the tissues (ie. autoimmune disease). This project aims to determine the importance of one such cytokine, called IL-27, in the production of antibodies in normal immune responses as well as in autoimmune disea ....Protective immune responses depend on supportive interactions between different white blood cell types. Signalling proteins called _cytokines� are a key means of communication between cells. Abnormal cytokine production can lead to poor protection against infection or immune attack against the tissues (ie. autoimmune disease). This project aims to determine the importance of one such cytokine, called IL-27, in the production of antibodies in normal immune responses as well as in autoimmune diseases like Lupus.Read moreRead less
Understanding The Pathogenesis And Heterogeneity Of Autoimmunity As Failure Of Multiple Steps
Funder
National Health and Medical Research Council
Funding Amount
$504,023.00
Summary
Autoimmune diseases like diabetes, thyroid disease or rheumatoid arthritis affect around 1 in 15 people in Australia. It is clear that defects in a number of different genetic mechanisms can contribute to the development of autoimmunity. But it is currently not clear how these different mechanisms need to interact to prevent the onset of disease. This grant seeks to understand these interactions and how defects in two or more tolerance mechanisms can lead to autoimmunity.
MicroRNA Networks That Safeguard The Functional Program Of Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$457,941.00
Summary
A newly discovered group of molecules termed microRNAs are thought to function as rheostats for the activity of genes. We have shown that these molecules are critical for the function of an immune cell type termed regulatory T cells. Without these cells, the immune system is unable to prevent uncontrolled and destructive inflammation. This proposal aims to utilize diverse technologies to uncover the precise molecular mechanisms by which microRNAs safeguard the function of regulatory T cells.
Intra- And Intercellular Spreading In Shigella Pathogenesis
Funder
National Health and Medical Research Council
Funding Amount
$216,318.00
Summary
Each year Shigella flexneri bacteria cause over 167 million episodes of dysentery and over 1 million deaths worldwide, under conditions of poor sanitation, in both developed and developing countries. No vaccines are available, and resistance to antibiotics is common. This project will study the a key part of the machinery that allows bacteria use to cause disease, and also to identify drugs that block the machinery which can in future be used to treat infection by these bacteria.
Organ-specific Autoimmunity: The Role Of The Thymus And Periphery In Shaping The Gastric-specific T Cell Repertoire
Funder
National Health and Medical Research Council
Funding Amount
$579,763.00
Summary
The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. White blood cells, called T lymphocytes are responsible for attacking our own tissues in autoimmune diseases. Our studies will employ a range of molecular, genetic and imaging technologies to track the rare and potential harmful white blood cells. Our studies should reveal the me ....The immune system normally protects against invasion by pathogens such as harmful viruses and bacteria. In autoimmune diseases the same mechanisms that are used to protect us are erroneously targeted to our own tissues. White blood cells, called T lymphocytes are responsible for attacking our own tissues in autoimmune diseases. Our studies will employ a range of molecular, genetic and imaging technologies to track the rare and potential harmful white blood cells. Our studies should reveal the mechanisms by which these self destructive T lymphocytes are silenced in healthy individuals on the one hand, and on the other hand escape to cause destruction in individuals with autoimmune diseases. This fundamental information will allow the development of therapeutic strategies to selectively turn-off these destructive T lymphoctyes in individuals with autoimmune disease and thereby remove the damaging immune response and cure the disease.Read moreRead less