Identification of molecular and cellular mechanisms of autoimmune disease
The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory (DIL) is a group of multidisciplinary investigators within the CIMR spanning computational biology to basic immunology and focused on identifying, understanding and modulating therapeutically the aetiological pathways that cause the common autoimmune disease, type 1 diabetes (T1D).
In collaboration with my Co-Director, Linda Wicker, and the groups within the DIL, we aim to identify and characterise the function of genes that contribute to disease susceptibility in humans (see Linda’s research page for further achievements). For example, the T1D genes CTLA4, IL2R (CD25), BACH2, PTPN2, PTPN22, IFIH1, IL21 and IL2 (ImmunoBase.org) underpin the function of FOXP3+CD25+CD4+ regulatory T cells (Tregs) and their balanced activity to suppress potentially autoimmune T effector cells (Teffs). Enhancing Treg function and modulating Teffs are therapeutic targets in T1D and the subject of intense investigation, forming the basis of our Translational Medicine Group, which we have set up successfully in the past 12 months, led by Dr Frank Waldron-Lynch.
Previously, we reported that higher expression of CD25 on memory CD4+ T cells (determined by genotype), which provides homeostatic levels of IL-2 required for Treg activity, correlates with protection from T1D; hence ways of enhancing homeostatic IL-2 production could be therapeutic. We have been characterising Tregs and Teffs (and other cells, including naïve T cells) at the cellular and molecular levels with the aim of increasing Treg CD25 expression and activity. In the last 12 months, one major new approach has been the design and execution of our first mechanistic study: an in vivo analysis of the effects of administering ultra-low-dose IL-2 to T1D patients (Adaptive study of IL-2 dose on regulatory T cells in Type 1 diabetes; DILT1D; Chief Investigator, Frank Waldron-Lynch; http://www.clinical-trials-type1-diabetes.com/); in April 2014, only 12 months since DILT1D started, we have recruited all 40 patients and will be analysing and extending the results of this trial. This approach complements and contrasts with our studies of gene-to-phenotype (http://www.cambridgebioresource.org.uk/) and case versus control immunophenotypic alterations in that we can study patients’ immune systems within an individual across time, with reduced assay variation observed in comparisons across individuals.
We study other genetically identified pathways, for example, the IL-6 pathway. We have shown that an allele of an amino acid-changing DNA polymorphism in the IL-6 receptor gene protects from T1D and several other diseases by lowering signalling through this proinflammatory receptor. Furthermore, we have shown using bioinformatics (Olly Burren) — in particular, the ImmunoBase database we have created to facilitate cross-disease analyses (https://www.immunobase.org/page/Welcome/display) — and statistical approaches (Chris Wallace) that the genetics of T1D overlap to the greatest extent with that of juvenile idiopathic arthritis (JIA). In a birth cohort of children at high risk of T1D we have discovered a type 1 interferon gene expression signature, which includes the T1D gene, IFIH1, that precedes autoantibody seroconversion. We have also discovered a biomarker for this IFN signature that can be analysed by flow cytometry analysis of SIGLEC-1 receptor expression on monocytes. We have reproduced and extended observations that vitamin D precursor can be metabolised to the active hormone in T cell activation cultures, which leads to an increase in the negative immune regulatory molecule CTLA-4 in Teffs. By correlating the most associated T1D risk SNPs across the known T1D loci, we have found that these SNPs often colocate with enhancer sequences and that this enrichment is most significant when foetal thymus tissue and primary T and B cells are analysed (http://www.broadinstitute.org/mammals/haploreg/haploreg.php).
Ongoing analyses of DILT1D have enabled us to secure funding from the Sir Jules Thorn Charitable Trust for a mechanistic study aimed at optimising the frequency of IL-2 dosing. We anticipate this trial will start in the summer of 2014 and be completed at the end of 2015. We will also continue phenotypic and functional studies in our ongoing characterization of the human immune system, including prioritisation of genes, molecules and pathways that might be therapeutically tractable.
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Dendrou, C.A., Plagnol, V., Fung, E.Y.M.G., Yang, J.H.M., Downes, K., Cooper, J.D., Nutland, S., Coleman, G., Himsworth, M., Hardy, M., Burren, O., Healy, B., Walker, N.M., Koch, K., Ouwehand, W.H., Bradley, J.R., Wareham, N.J., Todd, J.A. & Wicker, L.S. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nature Genet. 41, 1011–1015 (2009).
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Smyth, D.J., Plagnol, V., Walker, N.M., Cooper, J.D., Downes, K., Yang, J.H.M., Howson, J.M.M., Stevens, H., McManus, R., Wijmenga, C., Heap, G.A., Dubois, P.C., Clayton, D.G., Hunt, K.A., Van Hell, D.A. & Todd, J.A. Shared and distinct genetic variants in type 1 diabetes and celiac disease. New Engl. J. Med. 359, 2767–2777 (2008).