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
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.
Defining The Immunoregulatory Function Of Roqin: A Novel Gene Essential For Preventing Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$721,250.00
Summary
Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investi ....Lupus is a systemic autoimmune disease that carries significant morbidity and mortality. Virtually any organ can be affected, including kidneys, brain and blood. Lupus is the result of a breakdown in normal regulation of the immune system. Although there is clearly a significant genetic contribution to lupus, few causative genes have been found in humans with this disease. Recently, we discovered a novel mutation in a new gene (named roqin), that cases lupus in mice. Based on preliminary investigations and prediction based on the structure of Roqin, we suspect that this gene may be a key immune regulator. Specifically, it is likely to be involved in maintenance of immunological self-tolerance, which normally prevents development of autoimmunity. Mice carrying the Roqin mutation have an abnormality of their T cells, which causes them to be abnormally activated, divide more readily and survive for longer. Hyperactivated T cells induce B cells to proliferate and secrete antibodies against self-tissues that eventually lead to loss of platelets, kidney damage, enlarged spleen and lymph nodes, and early death. We now want to investigate precisely how Roqin causes abnormal T cell activation. The protein sequence of Roqin predicts the existence of two zinc finger domains that are highly conserved across species and play critical functions in regulating cell growth. One of the zinc fingers is a RING domain known to have a ubiquitin-ligase activity, which is known to play a crucial role in negative regulation of lymphocyte signalling, and maintenance of tolerance. The other zinc finger domain is known to be important for destabilizing mRNA of cytokines, thereby influencing communication between lymphocytes. Elucidation of this novel mechanism of disease will help understand the cause of human lupus. It will also provide clues about more specific drug therapies that might be more efficacious, and carry less toxicity than those currently available.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.