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Diabetes. 2017 Feb;66(2):460-473. doi: 10.2337/db16-0671. Epub 2016 Nov 21.

Primary Human and Rat β-Cells Release the Intracellular Autoantigens GAD65, IA-2, and Proinsulin in Exosomes Together With Cytokine-Induced Enhancers of Immunity.

Author information

1
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
2
Graduate Program in Biotechnology and Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
3
Proteomics Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
4
Bio-Electron Microscopy Core Facility, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
5
Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
6
Diabetes Research Institute, Istituto di Ricovero e Cura a Carattere Scientifico, San Raffaele Scientific Institute, Milan, Italy.
7
Institute of Molecular Engineering, University of Chicago, Chicago, IL.
8
Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
9
Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland steinunn.baekkeskov@epfl.ch.

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.

PMID:
27872147
DOI:
10.2337/db16-0671
[Indexed for MEDLINE]
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