Jayne Danska, PhD
Genetics & Genome Biology
University of Toronto
Professor, Medical Biophysics, Institute of Medical Sciences
Faculty of Immunology
For more information, visit:
- Immunogenetics of Type 1 diabetes
- Autoimmune disease
- Lymphoblastic leukaemia/lymphoma
- Mouse models
- Genomic instability
Type 1 diabetes:
Our work is predicated on the idea that mechanisms of T1D immunogenetic regulation in laboratory animals are shared with, and can provide insight into the human disease. There are many similarities between the T1D syndromes that develop in nonobese diabetic (NOD) animal models and humans. Some of the disease susceptibility genes that have been identified in humans by candidate gene and genome-wide association studies are shared between disease-prone humans and NOD animal models. Our objective is to understand progression of the autoimmune response that results in the death of b-islet cells in type 1 diabetes (T1D), and to identify genes and environmental factors that control these events. We developed quantitative assays to examine mediators of islet inflammation identifying the early involvement of specific T-cell subsets and three distinct phases in the process (J.Immunol 154:2969) and identified T-cell cytokine bias in the early islet infiltrates imprints the sex dependent incidence of male and female T1D (J.Immunol. 158:2414). Analysis of T and B lymphocytes revealed that both cell types were systemically activated in NOD compared to other strains and that these immune traits were under separate genetic control (J.Immunol. 167:7169; J.Immunol. 2010/04/20).
Identification of T1D genetic risk in human genes has relied on a diabetes as a clinical endpoint. We identified pre-clinical phenotypes including T-cell recruitment to early islet lesions, and mapped these to specific diabetes loci (Idd) providing the first assignment of Idd5 and Idd13 loci to defined steps in early T1D pathogenesis (Amer. J. Hum. Genet. 67:67). We subsequently identified Idd13 as the locus controlling an innate immune recognition system through which SIRPa expressed on macrophages. Since there is a strong female bias exists in the NOD T1D model, we analyzed genetic control of T1D in both sexes. Progression to severe islet inflammation was controlled by the Idd4 and Idd9 loci (J.Immunol. 174:7129). We showed that Idd4 displayed sex-specific locus effects in type 1 diabetes, the first defined sex-specific genetic effect in this model (J.Immunol 176:2976): Fine mapping, genomic sequencing and gene expression microarray analysis provided a Idd4.1 interval that regulates the type 1 interferon innate immune pathway in macrophages and dendritic cells and a second locus Idd4.2 that displayed sex-specific epistatic interaction with Idd4.1 (Diabetes 55:3611). These data reveal the complex genetic architecture underlying T1D in the NOD model.
Genomic instability in lymphoblastic cancer:
The major long-term goal of our research program is to understand how defects in the way cells detect and repair damaged chromosomes promote genetic instability and contribute to cancer.
Broken chromosomes are dangerous to cells and all animals have systems to detect and repair then. Human and rodent cells have systems that kill cells in which broken chromosomes persist. Research from model organisms, as well as in human cells, demonstrate that cancer cells are frequently defective in these DNA damage detection and repair systems.
We have developed mouse models in which genes that control components of the DNA damage response pathways have been mutated and shown that these animal models are cancer prone. What is surprising is that, despite the role of DNA damage detection and repair in all cell types, the only tumours observed in these animal models are lymphoma and lymphoblastic leukaemia.
We have identified one of the reasons for this tumour bias. The DNA repair pathways responsible for maintaining genetic stability of all cells are uniquely required for an ordered chromosome "splicing" that joins together gene segments in developing lymphocytes. The assembled "antigen receptor" genes code for proteins vital to immune recognition and clearance of foreign microbes (bacteria and viruses). Thus, while antigen receptor gene assembly is essential, it can compromise genetic stability of lymphocytes.
We have developed methods to "track" the fate of a broken chromosome of mouse lymphocytes to understand how defects in DNA damage response pathways affect cancer progression in these animals. In addition, we have established a spontaneous mouse model of a serious complication of human leukaemia, invasion of the brain by leukaemia cells. These models provide an opportunity to identify genetic pathways that promote leukaemia development in children and adults, to define genetic "markers" that will improve prediction of risk for spread of leukaemia into the brain and to identify targets for therapeutic intervention.
Severe combined immune deficient (SCID) animal models are defective in double-strand DNA break (DSB) repair and V(D)J coding joint formation, resulting in arrested lymphocyte development. We demonstrated that the repair activities in V(D)J recombination are inducible by DNA damage (Science 266:450) and that the p53 checkpoint is activated by a physiological recombination process that protects developing lymphocytes from transformation (Genes & Develop.,10:2038). SCID mutation occurs in Prkdc encoding the DNA-dependent protein kinase (DNA-PK), where we identified SCID as a nonsense mutation in the C-terminal kinase domain protein. (Mol. Cell. Biol. 16:5507). Radiation induced DNA-PK-independent repair facilitated oncogenic misjoining of V(D)J breaks in T-cell precursors. (Mol. Cell. Biol. 21:400). V(D)J breaks contributed to translocations of IgH/c-Myc in acute lymphoblastic leukemia (ALL) from p53/Prkdc-deficient animal models. We also developed a related mouse model that developed CNS leukemia, providing a novel spontaneous model for this frequent complication of human ALL Cancer Cell 3:37. We are working to identify the molecular mechanisms underlying early B-cell lymphoblastic leukemia and CNS dissemination in mouse models and humans through a collaborative program. We have focused on the intracellular signaling pathways that govern cell survival, differentiation or death fate decisions in normal and neoplastic lymphoid cells and the molecular pathways operate in leukemic initiation and progression. The objective of this program is to functionally translate knowledge gained in mouse models to primary human leukemia to support future clinical trials.
Normal and leukemic hematopoetic progenitors:
Graft failure in hematopoietic stem cell (HSC) transplantation occurs despite donor-host genetic identity of Human Leukocyte Antigens, suggesting that additional factors modulate engraftment. We found that the NOD background allowed superior engraftment of human HSC compared to other strains carrying equivalent immunodeficiency mutations. We used positional genetics to characterize the molecular basis for this strain-specificity and found that the NOD allele of Sirpa conferred human hematopoietic support. NOD SIRP-α demonstrated enhanced binding to the human CD47 ligand, and its expression on animal model macrophages was required for human hematopoietic support. Thus, we have identified Sirpa polymorphism as a potent genetic determinant of human HSC engraftment (Nat Immunol. 8:1313). Based on these results we have undertaken pre-clinical development of protein therapeutics targeted to the to SIRPa-CD47 axis to enhance normal hematopoetic stem cell engraftment in clinical transplant settings and to blunt homing and dissemination of acute myeloid leukemia (see patents).
Future Research Interests
Type 1 diabetes:
We are integrating genome-wide analyses of rodent and human T1D in a functional genomics program with the goal of identifying the genetic pathways that confer susceptibility to the disease. The studies will advance the identification and functional analysis of human T1D susceptibility genes, and assist in prediction and development of targeted therapies for prevention and treatment of the disease.
- Canadian Genetic Disease Network
- Canadian Institutes of Health Research (CIHR)
- Genome Canada
- National Cancer Institute of Canada (Canadian Cancer Society)
- The Juvenile Diabetes Research Foundation
Type 1 diabetes
Takenaka K, Prasolava TK, Wang JC, Mortin-Toth SM, Khalouei S, Gan OI, Dick JE, Danska JS. (2007) Polymorphism in Sirpa modulates engraftment of human hematopoietic stem cells. Nat. Immunol. 2007 Nov 4; [Epub ahead of print]
Ivakine EA, Mortin-Toth SM, Gulban OM, Valova A, Canty A, Scott C, Danska JS. (2006) The idd4 locus displays sex-specific epistatic effects on type 1 diabetes susceptibility in nonobese diabetic mice. Diabetes. 2006 Dec;55(12):3611-9.
Ivakine EA, Gulban O, Mortin-Toth SM, Scott C, Surrell D, Canty A, Danska JS. (2006) Molecular genetic analysis of the Idd4 locus implicates the interferon response in Type 1 diabetes in susceptibility of NOD mice. J. Immunol. 2006 Mar 1;176(5):2976-90.
Ivakine, E. A., Gulban, O., Mortin-Toth, S.M., Wankiewicz, E., Scott, C., Spurrell, D., Canty, A., and Jayne S. Danska. Molecular analysis of the Idd4 locus implicates the interferon response in Type 1 diabetes susceptibility of the NOD mouse. Journal of Immunology. 176: 2976-2990. (2006).
Ivakine,E.A., S.M. Mortin-Toth, O. Gulban A. Valova, A. Canty, and Jayne S. Danska. The Idd4 locus displays sex-specific epistatic effects on type 1 diabetes susceptibility in nonobese diabetic mice. Diabetes. 55(12): 3611-9. (2006).
Ivakine EA, Fox CJ, Mortin-Toth SM, Canty A, Walton DS, Paterson AD, Aleksa K, Ito S, Danska JS. (2005) Sex-specific control of type 1 diabetes pathogenesis by the Idd4 locus in the NOD mouse. J Immunol. 174(11):7129-40.
Ivakine, E.A. Fox, C.J., Mortin-Toth, S.M., Canty, A.,Walton, D.S., Paterson, A.D., Aleksa, K., Ito, S., and J.S. Danska. Sex-specific regulation of the Type 1 diabetes by the Idd4 locus in the NOD mouse. Journal of Immunology. 174:7129-7140. (2005).
Yuan, J.S., Tan, J.B., Visan, I., Matei, I., Urbanellis, P., Xu, K., Danska, J.S. Egan, S.E. and C.J. Guidos. 2010. Lunatic Fringe prolongs Delta/Notch induced self-renewal of committed αβ T cell progenitors. Blood, 117: 1184-1195. (2011).
Danska, J. S. and Poussier, P. After the GWAS rush: nuggets of insight into the pathogenesis of autoimmune disease. Seminars in Immunology: 21:313-317. (2009).
Matei IR, Gladdy RA, Nutter L, Guidos CJ, Danska JS (2007)ATM deficiency disrupts Tcra locus integrity and the maturation of CD4+CD8+ thymocytes. Blood. 109(5):1887-96.
Matei I.R., Gladdy R.A., Nutter L.M., Canty A., Guidos C.J. *, Danska J.S.*. ATM deficiency disrupts TCRα locus integrity and the maturation of CD4+CD8+ thymocytes. Blood. 109(5): 1887-96. (2007).
Curry, J.D., Schulz, D., Guidos, C.J., Danska, J.S., Nutter, L., Nussenzweig, A., Schlissel, M.S. Chromosomal reinsertion of broken RSS ends during T cell development. Journal of Experimental Medicine. 204(10): 2293-303. (2007).
Takenaka K., Prasalova, TK., Wang, J.C., Mortin-Toth, S.M., Khalouei S, Gan, O.I., Dick, J.E. & Danska J.S. Polymorphism in Sirpa modulates engraftment of human hematopoeitic stem cells. Nature Immunology. 8(12):1313-23. Epub 2007 Nov 4.
Gladdy RA, Nutter LM, Kunath T, Danska JS, Guidos CJ (2006) p53-independent apoptois disrupts early organogenesis in embryos lacking both ataxa-telangiectasia mutated and Prkdc. Mol Cancer Res. 4(5): 311-8.
Gladdy, R.A., Nutter, L.M. J., Kunath, J., Danska, J.S.*, and C.J. Guidos*. p53-independent apoptosis disrupts early organogenesis in embryos lacking ATM and Prkdc. Molecular Cancer Research. 4: 311-318. (2006)
Matei IR, Guidos CJ, Danska JS (2006) ATM-dependent DNA damage surveillance in T-cell development and leukemogenesis: the DSB connection. Immunol Rev. 209:142-58.
Matei, I., Guidos, C and J.S. Danska. ATM-dependent DNA damage surveillance in normal and neoplastic T cell development. Immunological Reviews: 209: 142-158. (2006).
Gladdy RA, Taylor MD, Williams CJ, Grandal I, Karaskova J, Squire JA, Rutka JT, Guidos CJ, Danska JS. (2003) p53-independent apoptois disrupts early organogenesis in embryos lacking both ataxa-telangiectasia mutated and Prkdc The RAG-1/2 endonuclease causes genomic instability and controls CNS complications of lymphoblastic leukemia in p53/Prkdc-deficient mice. Cancer Cell. 3(1):37-50.