Links Between Inflammatory Activity, Autoantibodies, And Cardiovascular Disease In Patients With SLE.
Funder
National Health and Medical Research Council
Funding Amount
$32,003.00
Summary
People with lupus are at increased risk of heart attack and stroke. For women aged 30-44 the risk is as much as fifty times higher than in women without lupus. Only some of this risk is due to well known factors like high blood pressure and cholesterol. We are looking at other possible causes of heart attack and stroke in people with lupus - with blood tests and heart scans. We hope this will identify who is at risk and what can be done to prevent them from suffering a heart attack or stroke.
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
Characterisation Of An In-vivo Thrombosis Animal Model Of The Antiphospholipid Syndrome Using Beta 2-GPI KO Mice
Funder
National Health and Medical Research Council
Funding Amount
$467,310.00
Summary
The antiphospholipid syndrome is an autoimmune condition characterised by the presence of thrombosis and recurrent miscarriage. The disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2- Glycoprotein I. This protein has been thought to be important in controlling the clotting system in humans and other mammals. However, the experiments that have been designed to look at the function of this protein have looked at its function in the test tube. The ....The antiphospholipid syndrome is an autoimmune condition characterised by the presence of thrombosis and recurrent miscarriage. The disorder is characterised by circulating antibodies which bind a protein in the blood known as Beta 2- Glycoprotein I. This protein has been thought to be important in controlling the clotting system in humans and other mammals. However, the experiments that have been designed to look at the function of this protein have looked at its function in the test tube. The exact role of Beta 2-GPI in the body, has not been determined. A way of looking at the function of this protein in the body would be if you eliminated the protein from an animal such as a mouse. By sophisticated molecular biology techniques 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 are an ideal animal model to examine the function of Beta 2-GPI. Experiments outlined in this proposal will examine the role of Beta 2-GPI in clotting, atherosclerosis and the effect of production of antibodies to Beta 2-GPI in these animals. In addition, since current treatment of patients that have these antibodies consists of long term, sometimes lifelong, treatment with drugs that thin the blood which have potential side effects, we are investigating a novel treatment approach which is directed at eliminating the antibodies that bind Beta 2-GPI. If one could eliminate the antibody production to Beta 2-GPI by these patients there would not be a need for lifelong treatment with drugs such as heparin which thins the blood and there would thus be a reduction in the problems with these medications. To do this we have obtained a specialised chemically modified portion of Beta 2-GPI that has already been shown to work in preliminary experiments.Read moreRead less
Initiation And Diversification Of Systemic Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$200,749.00
Summary
One of the striking findings in autoimmune diseases such as systemic lupus erythematosus and Sjogren's syndrome is the presence in the blood of autoantibodies reacting with certain proteins or autoantigens. The best known autoantigens are termed La and Ro and are important diagnostic markers in these two common conditions. It appears that the immune response starts against Ro and then spreads to La over time, a process known as epitope spreading. There is emerging evidence in Sjogren's syndrome ....One of the striking findings in autoimmune diseases such as systemic lupus erythematosus and Sjogren's syndrome is the presence in the blood of autoantibodies reacting with certain proteins or autoantigens. The best known autoantigens are termed La and Ro and are important diagnostic markers in these two common conditions. It appears that the immune response starts against Ro and then spreads to La over time, a process known as epitope spreading. There is emerging evidence in Sjogren's syndrome that the severity of this condition is related to the degree of epitope spreading to Ro and La, which in turn is controlled by the genetic background of the individual. We therefore wish to study the initiation of the autoimmune response to Ro and the factors which influence spreading or diversification to La, using a mouse model of La-Ro autoimmunity which we have developed. In addition, we shall investigate the potential role of a recently identified gene in a large group of patients with Sjogren's syndrome. We believe this gene may control the epitope spreading and expression of disease. The role of other molecules called chaperones (which bind to Ro) and complement (involved in clearing dead cells which may trigger autoimmunity) will also be studied. The ultimate goal of the work is to develop ways of blocking the epitope spreading which should ameliorate the disase and patients' symtpoms.Read moreRead less
Functional Genomic Analysis Of NK And NKT Cell Immune Control Of Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$692,040.00
Summary
The major populations of white blood cells responsible for learned immunity to 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 disease. These diseases include type 1 diabetes, lupus, and anaemia, and collectively represent the third commonest cause of morbidity and mortality in humans. The major reas ....The major populations of white blood cells responsible for learned immunity to 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 disease. These diseases include type 1 diabetes, lupus, and anaemia, and collectively represent the third commonest cause of morbidity and mortality in humans. The major reason why autoimmunity occurs is thought to be due to a failure in the mechanisms responsible for controlling such unwanted responses. Two other populations of white blood cells are involved in this regulation, termed NK and NKT cells, each of which release important cell hormones. The current project is designed to test whether defects in NK and NKT cells lead to autoimmune disease. For this purpose a special strain of mice (NOD mice) will be used. The reasons for their selection are: 1) they are highly susceptible to a range of autoimmune diseases including diabetes, lupus and anaemia, and 2) we and others have found that they are deficient in both NK and NKT cells. The proposed experiments are divided into two groups, one designed to characterise the nature of the defects in these cells and the other to identify the genes responsible for them. In this way it should be possible to shed light on the genetic basis of autoimmune diseases in general. The approach to be used involves sophisticated techniques of genetic analysis, which require production of special congenic lines of mice. These mice are like NOD mice but carry in addition to NOD genes genetic regions from a non-autoimmune strain with the potential to correct the defects in NK and NKT cells. In this way, it should be possible to pinpoint the disease susceptibility genes involved in causation of autoimmunity and to work out how they affect NK and NKT cells.Read moreRead less
Pathophysiological Mechanisms In The Antiphospholipid Syndrome: B2GPI Regulation Of FXI-FXIa
Funder
National Health and Medical Research Council
Funding Amount
$530,591.00
Summary
The major protein that the antibodies in the antiphospholipid syndrome (APS) bind is called Beta 2-GPI. Antibodies to Beta 2-GPI are associated with recurrent miscarriage, intrauterine growth retardation, clots and stroke. Treatment of patients with the APS are treated with medication that has significant side effects. The development of more targeted and effective therapies for the APS requires a greater understanding of how the antibodies cause their effects, which is addressed in this study.
Genetic Pathology Of Roquin In Human Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$495,466.00
Summary
Lupus is a life-threatening disease in which immune responses normally targeted at germs are directed at tissue in the body. We have discovered a mouse model of lupus and elucidated an important pathway that determines whether immunity is directed at the body or at germs. Building on recent progress in understanding the genetic variation between individuals, we will use the information obtained from the mouse model to investigate the genes that regulate this pathway in people with lupus.
Dissecting The Role Of The Lyn Tyrosine Kinase In B Cell Differentiation And The Development Of Autoimmunity.
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune diseases include more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more effective treatments. The Lyn tyro ....The immune system has to be capable of responding to an unlimited array of pathogens, but at the same time remain unresponsive to, or tolerant of self-antigens. A breakdown in the tolerance to self-antigens results in autoimmunity. Autoimmune diseases include more than 70 chronic disorders that affect about 1 in 20 people in the Western population. Improving our understanding of the mechanisms that underlie autoimmune disease is essential for the design of more effective treatments. The Lyn tyrosine kinase is a member of a family of genes that participate in transmitting information across the cell membrane. This enzyme is expressed in blood cells, and is involved in mechanisms pertaining to infection, immunity and allergic responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn (Lyn-deficient mice) and one that expresses an activated form of the Lyn enzyme (Lyn-up mice). We have found that both strains of mice develop autoimmune disease with characteristics similar to the human autoimmune disease systemic lupus erythematosus (SLE). These studies suggest that Lyn is an important severity gene in autoimmunity. In this study we will examine in detail the role that Lyn plays in B cell development, function and autoimmunity, and we intend to identify the pathways that lead to autoimmune disease in Lyn mutant mice. On completion of these studies we will have developed a catalogue of the molecules and pathways perturbed in Lyn mutant mice. These studies will greatly improve our knowledge and understanding of the mechamisms behind certain autoimmune diseases, and may indeed lead to improved diagnosis, prognosis and treatment of patients with these conditions.Read moreRead less