The main scientific interest of the Autoimmune Genetics Laboratory is in understanding the causes of immune pathology. The ideal state of the immune system is one of balance, where immune reactions are strong enough to clear tumours and infections, and yet controlled enough to prevent responses towards self and harmless foreign antigens. As coordinators of immune activity, the immunogenic/tolerogenic balance of T cells is critical to maintaining this pathology-free state.
The key difficulty in maintaining a balance of immune activity is the mechanism by which T cells, as part of the adaptive immune system, recognise antigens. Unlike the Toll-like receptor system, where specific receptors have evolved to bind specific foreign antigens, the T cell receptor (TCR) requires random generation of specificity at the genomic level. This creates the possibility of generating TCRs specific for antigens which the host has never encountered (anticipatory immunity), but also generates the risk that TCRs will be made which, by chance, bind inappropriate antigens. Elaborate processes of thymic and peripheral tolerance, only partially understood, have therefore needed to evolve in order to create immune balance. The evolution of immune balance is further complicated by the necessity of T cells to develop in the absence of their required targets – the only example of receptor avidity being forced to evolve in the absence of its essential ligand.
Despite the evolution of complex immune tolerance mechanisms, some individuals do develop immune pathologies. These can occur due to an overly active immune system, producing autoimmunity or allergy, or a poorly effective immune system, resulting in a failure to control infections or cancers. While these immune pathologies can occur due to simple genetic traits (such as mutations in the gene AIRE), the vast majority are complex traits, with the interaction of multiple genetic and environmental effects influencing the predisposition of the individual to immune pathology.
In the Autoimmune Genetics laboratory we are interested in understanding the cellular and molecular basis of immune tolerance mechanisms and failure. In order to dissect the mechanistic basis of immune balance we use the power of genetics. In ‘reverse genetics’ studies the role of a gene is studied by genetically increasing or decreasing its function. This approach is the simplest way to study the biology of a single gene, however only genes which are suspected to be involved in a trait can be tested. By contrast, we are interested in the phenotype of immune pathology. We therefore use a ‘forwards genetics’ approach of taking mouse strains with a genetic predisposition to immune pathology and then working out how this is controlled and why those genetic variations cause pathology. The key advantage to this approach is that we let the genome tell us which genes are important for our phenotype, allowing us to discover novel genes and mechanisms involved in the prevention of immune pathology.
The Autoimmune Genetics Laboratory is supported by grants from the VIB, University of Leuven, European Research Council, Juvenile Diabetes Research Foundation, the FWO and IWT.