Ontogeny Of Toll (TLR) Function In Normal And Allergic Children: The Impact Of Microbial-rich Environments
Funder
National Health and Medical Research Council
Funding Amount
$387,489.00
Summary
Reduced exposure to bacteria during early life has become a leading candidate to explain the escalating rate of allergic disease. Despite this, the development and maturation of the pathways involved in normal recognition of bacteria in children has not been explored. In this proposal we set out to address this critical shortcoming in both normal and allergic children. Mapping normal maturation of such pathways will help us to identify better early markers of allergic disease.
Fine Mapping Of Genes Underlying Asthma And Eosinophilia
Funder
National Health and Medical Research Council
Funding Amount
$278,000.00
Summary
Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors are known to be important modifiers of disease risk, and several genes have been reported in the literature as being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group, one of asthma in families, the other of healthy adolescent t ....Asthma is the fourth most common chronic disease in Australia, and is increasing in incidence. Genetic factors are known to be important modifiers of disease risk, and several genes have been reported in the literature as being involved in either causing asthma or altering response to therapy. Immunoglobulin E (IgE) level and eosinophil count are two factors known to be increased in the blood of asthmatics. In two studies by our group, one of asthma in families, the other of healthy adolescent twins, we showed these measures to be genetically linked to two different regions in the genome. Closer examination of these regions found several genes that might be responsible for the linkage. In the present study, we plan to test which of these candidate genes actually causes elevated IgE level or eosinophil count. The approach is to compare the frequency of a putative gene in a child expressing that phenotype to that in their parents. Each child receives one copy of a gene from the father, and one from the mother, making up a complete genotype (two possibly different versions or alleles of the gene). Since each parent transmitted only one allele to the child, the remaining allele from each parent can be used to create a normal control genotype, that is guaranteed to come from the same ethnic background as the asthmatic child. Therefore, we will collect replacement blood samples in those familes where all the previously DNA has been used up in our earlier study. We will extract DNA, and measure the genotypes of parents and children at the 6 genes in our two regions that we think most likely to be involved in eosinophil count or IgE level. This family based test will allow us to decide which genes are genuinely associated with asthma in our population. We will also test if these genes interact with other genes thought to be asthma risk factors. Identification of novel genes involved in asthma will help understand and ultimately treat this condition.Read moreRead less
I am a paediatric allergist and immunologist investigating pathways involved in normal immune development and how these differs in infants who develop allergic disease.
Atopic dermatitis (AD) or atopic eczema is the third condition making up the atopic triad (asthma, hayfever and eczema). It usually has its onset before two years of age. It is common, affecting approximately 10% of Australian children and 7% of Australian adults, and is increasing in prevalence. As with asthma, genes are known to be important in its causation, and several different genes have been reported to be involved by different investigators. These findings are not always repeatable in di ....Atopic dermatitis (AD) or atopic eczema is the third condition making up the atopic triad (asthma, hayfever and eczema). It usually has its onset before two years of age. It is common, affecting approximately 10% of Australian children and 7% of Australian adults, and is increasing in prevalence. As with asthma, genes are known to be important in its causation, and several different genes have been reported to be involved by different investigators. These findings are not always repeatable in different countries or ethnic groups. One, the mast cell chymase gene seems to be associated with AD in Japan, but not in Australia or Italy. However, this gene may be responsible only for AD where total serum Immunoglobulin E is low, roughly 20% of all AD. Therefore, the previous studies may not have included enough cases of this subtype to reliably detect the association. The present study aims to test all the published genes in two panels of families: one where both AD and asthma or hayfever are present in the family (180 families), the second where AD alone is present (100 families). We will also test for genetic linkage to particular regions of the genome, where the specific gene is yet to be identified, and for newly discovered gene variants in these regions that may be associated with AD. Confirming and refining the nature of genes involved in the causation of AD is useful for the basic understanding of biochemical pathways to disease and ultimately to the design of drugs to interfere with these pathways.Read moreRead less
B-1 B Cells As A Source Of Polyreactive IgE Antibodies, In Allergic Individuals
Funder
National Health and Medical Research Council
Funding Amount
$331,320.00
Summary
Allergic disease results from the actions of antibody molecules that are produced by cells called B cells. Over the last fifteen years, it has been realised that there are at least two B cell subsets, called B-1 and B-2 cells. The B-1 cells and their antibody products have many unusual features, and they have been implicated in some disease processes. We have recently completed studies that strongly suggest that B-1 B cells may play an important role in some allergic disease. We wish to compare ....Allergic disease results from the actions of antibody molecules that are produced by cells called B cells. Over the last fifteen years, it has been realised that there are at least two B cell subsets, called B-1 and B-2 cells. The B-1 cells and their antibody products have many unusual features, and they have been implicated in some disease processes. We have recently completed studies that strongly suggest that B-1 B cells may play an important role in some allergic disease. We wish to compare groups of patients defined according to their allergic conditions and age, to see whether B-1 B cell activity is associated with particular allergic diseases. We hypothesise that patients with allergic skin conditions have raised numbers of allergy-inducing B-1 cells. Such patients will be compared with those with allergies to inhalent allergens and others with food allergies. Studies will be performed in adult groups as well as in children, for B-1 B cell numbers are known to vary with age. As most of our understanding of the regulation of B cell function, in the context of allergic disease, has arisen from studies conducted with conventional B-2 cells, we also wish to reconsider aspects of B cell regulation. We are specifically interested in the regulation of the 'switching' of B-1 B cells, when they change from the production of antibodies of a 'non-allergic' type (IgM antibodies) to allergy-promoting IgE antibodies. We wish to determine whether the B-1 B cells of allergic individuals are particularly susceptible to such switching, when under the influence of regulatory molecules called cytokines. We expect that B-1 B cells will be associated with some, though not all allergic conditions, and that these cells will emerge as a new target for therapies. Such a finding would be most important. The development of new therapies will require a better understanding of the regulation of these cells, and this will be another important outcome of this project.Read moreRead less