The project, Functional Analyses of Autoimmune Disease Variants, is focused on three type 1 diabetes (T1D) susceptibility loci, CTLA4, PTPN22 and CD226 in humans and in mice. T1D is a major disease of children with an unexplained steady rise in incidence and increasing numbers of children diagnosed under age 5 years. The research proposed is fully integrated into the PPG activities and goals, and provides a platform to continue the highly productive, interdependent and synergistic collaboration amongst the PIs in Cambridge and Boston aimed at understanding the biological effects of T1D and autoimmune disease gene variants (that we have identified using genetic mapping). TlD gene variants will be studied ex vivo using fresh blood samples from a major resource of genetically-selectable, local healthy volunteers (the Cambridge BioResource) and in vivo, in precisely engineered NOD mouse models of T1D. The Ctla4, Ptpn22 and Cd226 KO alleles will be used to develop NOD strains to model human T1D. A mouse Ptpn22 variant that increases T1D will be a focus of mechanistic studies on the PTPN22 gene, which is part of a molecular pathway that affects multiple human autoimmune diseases. T cells having the susceptibility allele at Ptpn22 have a higher threshold of activation and at a population level fewer of the cells produce IL-2 when stimulated ex vivo. Since both human and mouse gene variants in the IL-2 pathway affect T1D susceptibility, experiments to study gene-gene interactions between the PTPN22 and IL-2 pathways in both species are proposed. Preliminary data indicate that the susceptibility allele at CTLA4, which decreases the expression of soluble CTLA-4, reduces the probability that Tregs will be activated. Overexpression of soluble CTLA-4 in primary T cells and cell lines will be one approach used to study the mechanism by which soluble CTLA-4 affects early events in T cell activation. Since variants at both the PTPN22 and CTLA-4 genes are proposed to alter T cell activation, gene-gene interactions between the PTPN22 and CTLA-4 pathways in both humans and mice will be investigated.
The mortality, morbidity and healthcare costs of type 1 diabetes are enormous. The identification of the genes and pathways that cause type 1 diabetes will allow the identification of early, inherited immunophenotypes or disease precursors that precede autoimmunity and that may be suitable argets or read-outs in ongoing or future clinical trials.
|Longbrake, Erin E; Hafler, David A (2016) Linking Genotype to Clinical Phenotype in Multiple Sclerosis: In Search of the Holy Grail. JAMA Neurol 73:777-8|
|Axisa, Pierre-Paul; Hafler, David A (2016) Multiple sclerosis: genetics, biomarkers, treatments. Curr Opin Neurol 29:345-53|
|Lowther, Daniel E; Goods, Brittany A; Lucca, Liliana E et al. (2016) PD-1 marks dysfunctional regulatory T cells in malignant gliomas. JCI Insight 1:|
|Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44:989-1004|
|Chastre, Anne; Hafler, David A; O'Connor, Kevin C (2016) Evaluation of KIR4.1 as an Immune Target in Multiple Sclerosis. N Engl J Med 374:1495-6|
|Marson, Alexander; Housley, William J; Hafler, David A (2015) Genetic basis of autoimmunity. J Clin Invest 125:2234-41|
|Kurtulus, Sema; Sakuishi, Kaori; Ngiow, Shin-Foong et al. (2015) TIGIT predominantly regulates the immune response via regulatory T cells. J Clin Invest 125:4053-62|
|Housley, William J; Fernandez, Salvador D; Vera, Kenneth et al. (2015) Genetic variants associated with autoimmunity drive NFÎºB signaling and responses to inflammatory stimuli. Sci Transl Med 7:291ra93|
|Fraser, Heather I; Howlett, Sarah; Clark, Jan et al. (2015) Ptpn22 and Cd2 Variations Are Associated with Altered Protein Expression and Susceptibility to Type 1 Diabetes in Nonobese Diabetic Mice. J Immunol 195:4841-52|
|Preusser, Matthias; Lim, Michael; Hafler, David A et al. (2015) Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat Rev Neurol 11:504-14|
Showing the most recent 10 out of 190 publications