title: Primary Human and Rat β-Cells Release the Intracellular Autoantigens GAD65, IA-2, and Proinsulin in Exosomes Together With Cytokine-Induced Enhancers of Immunity.
abstract: The target autoantigens in several organ-specific autoimmune diseases, including type 1 diabetes (T1D), are intracellular membrane proteins, whose initial encounter with the immune system is poorly understood. Here we propose a new model for how these proteins can initiate autoimmunity. We found that rat and human pancreatic islets release the intracellular β-cell autoantigens in human T1D, GAD65, IA-2, and proinsulin in exosomes, which are taken up by and activate dendritic cells. Accordingly, the anchoring of GAD65 to exosome-mimetic liposomes strongly boosted antigen presentation and T-cell activation in the context of the human T1D susceptibility haplotype HLA-DR4. Cytokine-induced endoplasmic reticulum stress enhanced exosome secretion by β-cells; induced exosomal release of the immunostimulatory chaperones calreticulin, Gp96, and ORP150; and increased exosomal stimulation of antigen-presenting cells. We propose that stress-induced exosomal release of intracellular autoantigens and immunostimulatory chaperones may play a role in the initiation of autoimmune responses in T1D.
authors.affiliation: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cianciaruso
authors.affiliation: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Phelps
authors.affiliation: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Miriella
authors.initials: M
authors.lastname: Pasquier
authors.affiliation: Proteomics Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Romain
authors.initials: R
authors.lastname: Hamelin
authors.affiliation: Bio-Electron Microscopy Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Davide
authors.initials: D
authors.lastname: Demurtas
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Alibashe Ahmed
authors.affiliation: Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Hirosue
authors.affiliation: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Institute of Molecular Engineering, University of Chicago, Chicago, IL.
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.affiliation: Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.affiliation: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Institute of Molecular Engineering, University of Chicago, Chicago, IL.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Hubbell
authors.affiliation: Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland steinunn.baekkeskov@epfl.ch.|Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Steinunn
authors.initials: S
authors.lastname: Baekkeskov
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D037282:Calreticulin / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D059865:Endoplasmic Reticulum Stress / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D055354:Exosomes / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology; D006239:Haplotypes; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000276:immunology; D016688:Mice, Inbred NOD; D046529:Microscopy, Electron, Transmission; D009924:Organ Culture Techniques; D011384:Proinsulin / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology*
chemical_list: D001324:Autoantigens; D037282:Calreticulin; D015804:HLA-DR4 Antigen; D018840:HSP70 Heat-Shock Proteins; D008081:Liposomes; D008562:Membrane Glycoproteins; C053387:endoplasmin; C050087:oxygen-regulated proteins; D011384:Proinsulin; C516862:PTPRN protein, human; C516863:Ptprn protein, mouse; C516864:Ptprn protein, rat; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2