Determinant Spreading And The Role Of The MHC Class II Region In Systemic And Organ-specific Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$140,570.00
Summary
Autoimmune diseases are among the most important group of disorders affecting the adult population. In these diseases the immune system damages organs and tissues producing widespread pathology (systemic autoimmunity such as Lupus erythematosus) or localised disease (organ-specific autoimmunity such as insulin dependent diabetes). We understand very little about how and why the immune system attacks the body's own tissues. This study examines how antibodies and T lymphocytes are formed against c ....Autoimmune diseases are among the most important group of disorders affecting the adult population. In these diseases the immune system damages organs and tissues producing widespread pathology (systemic autoimmunity such as Lupus erythematosus) or localised disease (organ-specific autoimmunity such as insulin dependent diabetes). We understand very little about how and why the immune system attacks the body's own tissues. This study examines how antibodies and T lymphocytes are formed against components located inside cells of the body. The study involves genetically modifying mice by introducing key human genes which influence the development of autoimmunity. In this way the role of these human genes can be examined experimentally without having to work exclusively on patients. We also hope that these mice might be important in creating new models of celiac disease and insulin dependent diabetes. The proposed experiments should tell us how these genes contribute to the development of autoimmune disease. This understanding could be relevant devising treatments and interventions to prevent autoimmune diseases.Read moreRead less
Novel Mechanisms And Targets In Neonatal Lupus: Clues To Systemic Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$428,250.00
Summary
Autoimmune diseases represent the third greatest clinical burden to the community after heart disease and cancer. Management of the diseases remains primitive because of our poor understanding of the disease mechanisms. Autoantibodies are one of the key markers of diseases such as lupus and Sj gren's syndrome, but their role in producing tissue damage is largely unresolved. However in the neonatal lupus syndrome, autoantibodies from the mothers cross the placenta and appear to cause inflammation ....Autoimmune diseases represent the third greatest clinical burden to the community after heart disease and cancer. Management of the diseases remains primitive because of our poor understanding of the disease mechanisms. Autoantibodies are one of the key markers of diseases such as lupus and Sj gren's syndrome, but their role in producing tissue damage is largely unresolved. However in the neonatal lupus syndrome, autoantibodies from the mothers cross the placenta and appear to cause inflammation of particular target organs such as the heart and skin in the babies. Neonatal lupus offers a unique opportunity to investigate the pathological role of autoantibodies and other factors (e.g. infection) in autoimmune diseases, and is likely to offer vital clues to lupus in adults. For example, the skin disease in babies with lupus mimics the cutaneous lesions in adult lupus patients. Recent work from our group using an animal model has shown that certain autoantibodies cross the placenta and bind to cells undergoing physiological death in the fetus, in the same organ distribution as human neonatal lupus. Using sophisticated imaging techniqes we can now trace the fate of maternal autoantibodies in the babies for the first time and understand how the target proteins in heart and skin become exposed to the damaging effects of these autoantibodies. We also believe that certain types of autoantibodies can directly alter contraction and electrical activity in the heart in babies with neonatal lupus, leading to heart block which can be fatal. We have already discovered similar functional autoantibodies in adult patients with Sj gren's syndome whose babies can also also develop neonatal lupus, and plan to characterise them using unique physiological assays in intact hearts. We will characterise the redistribution of antigenic proteins in cells in fetuses and the interaction of maternal autoantibodies with these proteins to cause tissue damage and functional heart block.Read moreRead less
The Role Of Myeloperoxidase In Adaptive Immunity And The Development Of Experimental Glomerulonephritis And Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
This proposal will explore the role of key defensive enzyme in white blood cells, myeloperoxidase. It participates in immune defence as well as autoimmune diseases including nephritis and arthritis. This study will define the mechanisms of its protective and injurious capacities in these diseases.
This project introduces a new biomarker in systemic lupus erythematosus termed an apotope. The aims are to study the diagnostic potential of an apotope of Ro60, a key target in lupus, together with its ability to initiate the disease and cause organ damage. The interaction of the Ro60 apotope with a novel protective factor called beta2-glycoprotein I will also be studied. These discoveries are likely to lead to new diagnostic tests and preventions for lupus and neonatal lupus.
Mechanisms Of Immune Complex-mediated Inflammation In The Cerebral Microvasculature
Funder
National Health and Medical Research Council
Funding Amount
$146,500.00
Summary
Immune complexes are formed when an antibody binds to the molecules it is directed against. Normally, this is important for fighting infection. However in some autoimmune diseases, inappropriate formation of immune complexes can be damaging to our own tissues. This damage occurs because immune complexes attract white blood cells to the areas where they form. Many tissues can be affected by this process. However, we know very little about the effects of immune complexes specifically in the brain. ....Immune complexes are formed when an antibody binds to the molecules it is directed against. Normally, this is important for fighting infection. However in some autoimmune diseases, inappropriate formation of immune complexes can be damaging to our own tissues. This damage occurs because immune complexes attract white blood cells to the areas where they form. Many tissues can be affected by this process. However, we know very little about the effects of immune complexes specifically in the brain. This is important because immune complexes are found in the brain in diseases such as lupus. Therefore the aim of this proposal is to determine how immune complexes induce damaging inflammation in the brain.Read moreRead less
Functional Analyses Of The Major Merozoite Surface Protein Of Malaria Parasites
Funder
National Health and Medical Research Council
Funding Amount
$70,285.00
Summary
In this project we aim to learn about the function of one of the leading malaria vaccine candidates, merozoite surface protein 1 (MSP-1). Although a promising candidate, little is known about the role of this protein in the invasion by parasites of red blood cells or of the likelihood that the parasites will adapt to avoid vaccines based on MSP-1. To address these issues we propose to use the powerful new technology of parasite transfection, that is the ability to insert DNA into parasites to sp ....In this project we aim to learn about the function of one of the leading malaria vaccine candidates, merozoite surface protein 1 (MSP-1). Although a promising candidate, little is known about the role of this protein in the invasion by parasites of red blood cells or of the likelihood that the parasites will adapt to avoid vaccines based on MSP-1. To address these issues we propose to use the powerful new technology of parasite transfection, that is the ability to insert DNA into parasites to specifically alter its genetic code. We have pioneered this technology and have developed many of the most effective tools for the process. Insight gained from these studies is likely to influence significantly the design and potential uses of MSP-1 as a vaccine to control malaria.Read moreRead less
Role Of Adhesion Molecules In Autoimmune Vasculitis
Funder
National Health and Medical Research Council
Funding Amount
$377,036.00
Summary
Lupus is a disease which causes inflammation and pain throughout the body. The inflammation is caused by white blood cells attacking the lining of blood vessels in tissues. The aim of this project is to understand the reasons why these white blood cells attack the blood vessel lining. This process is impossible to study in humans. However, there is a strain of mouse which is affected by a disease which is very similar to human lupus. This disease occurs spontaneously in these mice. Using a micro ....Lupus is a disease which causes inflammation and pain throughout the body. The inflammation is caused by white blood cells attacking the lining of blood vessels in tissues. The aim of this project is to understand the reasons why these white blood cells attack the blood vessel lining. This process is impossible to study in humans. However, there is a strain of mouse which is affected by a disease which is very similar to human lupus. This disease occurs spontaneously in these mice. Using a microscope, it is possible to study the tiny blood vessels which are affected by this disease in these mice . Under the microscope, it is possible to see the white blood cells as they undergo the process of attacking the blood vessel lining. Visualizing this attack then allows us to study it and determine which molecules are important in causing this damaging inflammatory response. Specifically I will examine diseased blood vessels in the skin and brain of these mice, two of the tissues most dramatically affected by this disease. This information should help us gain an increased understanding of lupus as it affects humans.Read moreRead less
Relationship Between Periodontal Disease And Rheumatoid Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$520,657.00
Summary
Periodontal (gum) disease and rheumatoid arthritis are two of the most common chronic inflammatory diseases affecting humans. These two diseases have remarkably similar patterns of tissue destruction. It is possible that individuals with chronic periodontitis may prime or predispose individuals prone to developing rheumatoid arthritis. Treatment of periodontal disease may help reduce the severity of rheumatoid arthritis.
Functional Genomic Analysis Of The NKT Cell Control Locus Nkt1 And The Bana3/Babs2 Lupus Susceptibility Locus
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
The major populations of white blood cells responsible for learned immunity are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body's own tissues, resulting in autoimmune diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as the brain, skin and especially the kidneys. Another population of ....The major populations of white blood cells responsible for learned immunity are the B cells, which make antibody against microorganisms like bacteria, and the T cells, which kill virally infected cells and help B cells produce antibody. The T and B cells occasionally attack the body's own tissues, resulting in autoimmune diseases such as lupus, in which antibodies are deposited in the tissues causing inflammation in organs such as the brain, skin and especially the kidneys. Another population of white blood cells, termed NKT cells, plays an important role in keeping the T and B cells in check, and we have found that these cells are deficient in an inbred mouse strain, NOD mice, which develop lupus after exposure to a particular type of bacteria, called mycobacteria. We have found that one of the major genes conferring susceptibility to lupus in these mice lies in the same genetic region as the major gene controlling NKT cell numbers, raising the possibility that the deficiency in NKT cells in this strain predisposes it to developing lupus. The experiments proposed for this project are divided into two groups. The first group test whether increasing NKT cell numbers by either injecting them, or else transferring genes that allow more to develop naturally, can affect the risk of developing lupus. The second group of experiments examine the potential roles of two specific genes which are in the genetic region of interest, and which we think might control both NKT cell numbers and lupus susceptibility. The approach to be used involves sophisticated techniques of genetic analysis, such as the use of mutant mice which carry genetic mutations near the relevant genes, and congenic mice, which are like NOD mice, but carry in addition to NOD genes, genetic regions from a non-autoimmune strain.Read moreRead less
Autoimmune diseases result from a complex interaction between multiple genes and environmental factors. Attempts to identify the genes involved have been largely unsuccessful because of this complexity. This project has chosen to focus on a particular subset of the genes that cause type 1 (autoimmune) diabetes - the subset that control a small population of regulatory white blood cells, termed NKT cells. The applicants have previously shown that a mouse strain prone to diabetes, the NOD mouse st ....Autoimmune diseases result from a complex interaction between multiple genes and environmental factors. Attempts to identify the genes involved have been largely unsuccessful because of this complexity. This project has chosen to focus on a particular subset of the genes that cause type 1 (autoimmune) diabetes - the subset that control a small population of regulatory white blood cells, termed NKT cells. The applicants have previously shown that a mouse strain prone to diabetes, the NOD mouse strain, is deficient in NKT cells and if they are replaced by transfusion, the mice are protected from disease. In selective breeding experiments, they have been able to show that the deficiency in NKT cell numbers is genetic, and have localised the chromosomal positions of these genes. Furthermore, they have produced specially bred lines of NOD mice that have normal copies of these genes and increased numbers of NKT cells. This project aims to identify the genetic coding sequences responsible for controlling numbers of NKT cells. It will use a combination of genetic mapping, specific breeding, gene analyses and the production of genetically modified organisms. The result of this study will be the identification of at least one of the genes that control NKT cell numbers. These gene(s) will then be studied in patients to determine if it plays a role in human disease.Read moreRead less