Autoimmune Genetics Laboratory

Target organ function and the determination of pathological outcome during autoimmunity

The Non-obese diabetic (NOD) mouse is one of the best studied models of polygenic autoimmunity. Similar to autoimmune human patients, the NOD strain is susceptible to multiple autoimmune diseases, with specific disease development depending on slight alterations in the environment and genetics. Diabetes in the NOD mouse is controlled by at least 20 different loci, with the large number of small genetic components making identification of the causative alleles extremely difficult.

Project funded by the JDRFIn order to overcome the difficulty of multiple loci, we can analyse the genetic control of a sub-phenotype that is functionally relevant to the development of diabetes. This project is focused on the variation that the NOD mouse strain has in the pancreas itself. Using a transgenic model of islet-specific cellular stress, we find that the NOD pancreas is weaker than that of other strains of mice, which may cause it to fail under a lower level of autoimmune stress. By dissecting the molecular basis of this weakness we hope to understand the contribution that variation in non-immunological tissues can make to the outcome of immune pathology.


Translating advances in mouse immunogenetics into human disease

Project funded by the ERCAdvances in sequencing technology allow forward genetic approaches, previously only realistic in model organisms, to be used for human disease. In this project funded by the European Research Council,  we analyse immunodeficiency and autoimmunity patients at both an immune phenotyping and genomic level, in order to search for new gene mutations capable of causing disease in humans.


Asymmetric regulation of the immune system

Foxp3+ regulatory T cells are a key cell type able to suppress the proliferation and function of CD4+ and CD8+ T cells, and possibly other cell types.  In the Autoimmune Genetics Laboratory we are investigating new lines of evidence which suggest that rather than acting as a general immune rheostat, Foxp3+ regulatory T cells has asymmetric impacts on the immune system, suppressing some arms of the immune response to greater extents than other.


A forward genetics approach to understanding Foxp3+ regulatory T cell biology

While Foxp3+ regulatory T cells are critical for establishing the balance of immunity, our understanding of the molecular control of this population, and hence our potential to intervene therapeutically, is very limited. In order to understand the molecular control of Foxp3+ regulatory T cells we are running a forward genetics screen for mutant mice with defects in the generation and function of this critical population. We use the mutagen ENU, which introduces single base-pair substitutions at random throughout the genome. When combined with an appropriate breeding and phenotypic screening strategy, this allows the dissection of the molecular basis of cellular traits. Due to the forwards genetics approach we are also able to discover previously unknown genes involved in the process which would not be discovered by traditional approaches.


The molecular basis of thymic involution

T cell development is a unique cellular process, requiring an anatomically distinct organ, the thymus. The thymus, essential for efficient differentiation, is highly active during during early life, but is reduced in size and function after puberty, reaching a remnant status in old age. The molecular control over this age-related involution is only weakly understood, and is a major focus for research in the Autoimmune Genetics Laboratory.