title: Polymorphism in the innate immune receptor SIRPα controls CD47 binding and autoimmunity in the nonobese diabetic mouse.
abstract: The signal regulatory protein (SIRP) locus encodes a family of paired receptors that mediate both activating and inhibitory signals and is associated with type 1 diabetes (T1D) risk. The NOD mouse model recapitulates multiple features of human T1D and enables mechanistic analysis of the impact of genetic variations on disease. In this study, we identify Sirpa encoding an inhibitory receptor on myeloid cells as a gene in the insulin-dependent diabetes locus 13.2 (Idd13.2) that drives islet inflammation and T1D. Compared to T1D-resistant strains, the NOD variant of SIRPα displayed greater binding to its ligand CD47, as well as enhanced T cell proliferation and diabetogenic potency. Myeloid cell-restricted expression of a Sirpa transgene accelerated disease in a dose-dependent manner and displayed genetic and functional interaction with the Idd5 locus to potentiate insulitis progression. Our study demonstrates that variations in both SIRPα sequence and expression level modulate T1D immunopathogenesis. Thus, we identify Sirpa as a T1D risk gene and provide insight into the complex mechanisms by which disease-associated variants act in concert to drive defined stages in disease progression.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada;
authors.forename: Andrea Sut Ling
authors.initials: AS
authors.lastname: Wong
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada;
authors.forename: Steven
authors.initials: S
authors.lastname: Mortin-Toth
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada;
authors.forename: Michael
authors.initials: M
authors.lastname: Sung
authors.affiliation: Department of Mathematics and Statistics, McMaster University, Hamilton, Ontario L8S4L8, Canada;
authors.forename: Angelo J
authors.initials: AJ
authors.lastname: Canty
authors.affiliation: Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada;
authors.forename: Omid
authors.initials: O
authors.lastname: Gulban
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford OX13RE, United Kingdom; and.
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G1X8, Canada; Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S1A8, Canada jayne.danska@sickkids.ca.
authors.forename: Jayne S
authors.initials: JS
authors.lastname: Danska
mesh_terms: D000818:Animals; D015551:Autoimmunity; D051928:CD47 Antigen / Q000235:genetics* / Q000276:immunology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006801:Humans; D007113:Immunity, Innate; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D022423:Myeloid Cells / Q000276:immunology / Q000473:pathology; D011110:Polymorphism, Genetic / Q000276:immunology*; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000235:genetics* / Q000276:immunology; D012307:Risk Factors; D015398:Signal Transduction; D019076:Transgenes
chemical_list: D051928:CD47 Antigen; C497895:Cd47 protein, mouse; D008024:Ligands; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic