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
Molecular Profiling Of The Immunoglobulin Proteome In Primary Sjögren’s Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$322,460.00
Summary
Primary Sjögren’s syndrome is a common autoimmune disease. The patients have high levels of circulating immunoglobulins (Igs) in their blood-a hallmark of the disorder. The applicant proposes to sequence these Igs and identify their so-called variable region molecular signatures. These signatures can then be used in a mass spectrometric-based diagnostic platform to identify unique clones in patients as early markers of the disease process, and hopefully lead to more relevant diagnostic markers.
Rogue B Cell Clones In Patients With Autoimmune Disease
Funder
National Health and Medical Research Council
Funding Amount
$916,670.00
Summary
Our immune system protects us from disease by producing antibodies. However, 5% of Australians suffer from an autoimmune disease where they produce “auto” antibodies, which attack their own organs. This research will study the cells (termed B cells) responsible for making autoantibodies to determine how they differ from B cells that defend against disease. The goal is to develop therapies that eliminate autoantibody producing B cells from patients while preserving the immune system.
T Helper Cytokines In Immunity And Organ-specific Autoimmunity
Funder
National Health and Medical Research Council
Funding Amount
$443,946.00
Summary
The overall goal of these studies is to identify mechanisms underlying the effects of cytokines on T cell-mediated immunity, how defects in these processes can result in organ specific autoimmune disease, and whether exploiting these mechanisms may result in improved therapies for individuals with autoimmune diseases. The proposed aims build on my previous work on interleukin-21 and interleukin-21-producing T helper cells in both immunity and autoimmunity.
How Does Disruption Of Serinc1 Expression Affect Lymphocyte Function And The Development Of Autoimmunity?
Funder
National Health and Medical Research Council
Funding Amount
$681,555.00
Summary
Autoimmune diseases affect up to 8% of the population. We have recently discovered a novel gene mutation in mice that results in increased levels of anti-nuclear antibodies, a hallmark of various autoimmune diseases in humans. The mutated gene, Serinc1, has not been previously implicated in autoimmune disease, but it is important for synthesis of key molecules in immune cells. This research proposal aims to determine how disruption of Serinc1 contributes to the development of autoimmune disease.
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