The Centre for Immunology and Allergy Research (CIAR) was established to advance basic and clinical research in the fields of immunology and allergy.
Researchers are investigating the cellular and genetic basis for major diseases of the immune system, autoimmunity, immune deficiency, chronic viral infection and atopy, especially by dissecting the immunologic genes of the human genome and studying effects of genetic variation on immune function.
Two large scale genome wide screens (GWS) for inherited susceptibility factors in multiple sclerosis, in which we play a major role, have been completed and discovered new genetic associations.
The screen carried out by the Australian New Zealand MS Genetics Consortium (ANZGene) identified CD40 and a novel region in chromsome12, published in Nature Genetics in June 2009 (ANZgene, 2009). We are now engaged in fine mapping the chromosome 12 region, and working out how CD40 affects MS.
The second GWS, in collaboration with the International Multiple Sclerosis Consortium and the Wellcome Trust, is the largest ever undertaken, and has identified virtually all the genes which increase risk by more than 20%. Thisstudy will be submitted for publication in mid 2010.
We aim to determine the basis for these new genetic associations in the next few years, and it is expected this knowledge will contribute to the development of new therapeutic strategies.
In addition to our group’s contribution to the genome screens, David Booth has led the associated gene expression studies, the largest such study in MS carried out to date.This work has identified aT cell activation signature characteristic of MS, andwhich may prove useful as a biomarker to monitor response to therapy, to predict who might be susceptible to MS and other autoimmune diseases, and define a molecular type of MS.
The IL-7R gene
IL-7R is the second gene unequivocally confirmed worldwide to be associated with MS susceptibility. We have shown that the MS-susceptibility variant of the gene produces more of a soluble form of this receptor, which can reduce cell-surface receptor signalling (McKay et al, 2008a).The IL-7R gene is produced in many cell types within the immune system, but how does the susceptibility variant cause a predisposition to MS?
Experiments have been aimed at determining the context in which the MS-susceptibility variant behaved most differently from the other IL-7R variants within the immune system. We examined T cells, important mediators of tissue damage or tissue protection in MS, in 9 different states of activation/differentiation. However, the greatest difference in behaviour of the MS-susceptibility variant of IL-7R was observed in dendritic cells, an important class of cells which process and present antigen to the immune system.
In dendritic cells IL-7R responds toTSLP signals to suppress autoimmunity, and we showed that dendritic cells with MS-susceptibility variant of IL-7R may receive less of this signal. The challenge is to use this knowledge to correct autoimmunity in MS. This work is now published in the Journal of Immunology (Hoe et al, 2010).
Our patent application for MS therapy is based on removing immune cells from a person with MS, and re-educating them viaTSLP signalling through IL-7R to prevent immune reactivity to central nervous system antigens in MS. We have secured funding for 2009 from Merck-Serono to examine new ways to generate tolerising dendritic cells in vitro using cytokines in combination with IL-7R signalling and other agents to suppress autoimmunity.
Molecular response to therapy
As part of our ARC Linkage project with Biogen-Idec we continued to provide Australia’s only IFN bioactivity service, which tests if people with MS using this therapy have a biological response to the drug, which is necessary if they are to respond to therapy. Over 2000 people have now had samples tested under this service.
In addition, we have recently shown that IL-7R is up regulated by IFN in peripheral blood cells in vitro, including both naïve and memory T cells.
However, this effect is not seen amongst individuals carrying the haplotype 4 IL-7R variant. We hypothesise that haplotype 4 carriers may be less responsive to the antiviral effects of IFN, and possibly the therapeutic effects of the drug (Hoe et al, Journal of Interferon and Cytokine Research, 2010).
Allergy and Asthma
During 2009 we continued our focus on PHF11, investigating how this gene contributed to the changes in the immune system in allergic individuals. We were the first group to independently confirm a link between the inheritance of specific genetic variants in PHF11 and the risk of developing allergic disease. Several recent studies from other research groups also support a link between heritable genetic variants in PHF11 and allergy.
We are at the beginning of a revolution in the understanding of the genetic basis of complex heritable disorders that can involve many genes interacting in a complex manner with the environment. This is being achieved by the use of genome-wide association studies, allowing scientists to evaluate differences in common genetic variants between thousands of healthy and affected individuals. Several genome-wide association studies have already been published on asthma and allergic eczema and an Australian genome-wide association study is currently being done, for which we have assisted in the collection of several hundred samples as part of a collaboration with the Childhood Asthma Prevention Study (CAPS).
Although such genome-wide association studies have the potential to deliver novel insights into the pathogenesis of allergy with the promise of improved diagnosis and therapy, much work must still be done to fully understand the function of many of the genes identified in these studies. The PHF11 gene is a good example of this, which was identified in a genetic association study prior to any knowledge of its function. Using an array of genetic, molecular and cell biological techniqueswe published the first functional study of PHF11 in 2008 and in 2009 we completed a new functional study of PHF11, providing additional detail on how PHF11 turns on the expression of genes inT-cells of the immune system.
New work from our laboratory on the function of PHF11 has now revealed an unexpected link to how cells cope with stress. A cell can encounter stress in a number of ways with one common route involving the cellular response to infection by viruses. This is particularly interesting as a recent genome-wide association study of asthma has identified a novel gene, called ORMDL3, that also appears to be important in how cells respond to stress. These findings are now leading us to examine the role of PHF11 in cells that are at the interface of contact with the environment; these include cells that line our airways and digestive system that come into contact with environmental irritants and infectious agents.
Since the response of our immune systems to these agents is determined in part by the inheritance of genetic variants in genes such as PHF11, the continued genetic and functional investigation of genes linked with allergy will be play an important role in understanding the risk of developing allergies.