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:

Cianciaruso Chiara12,Phelps Edward A.1,Pasquier Miriella1,Hamelin Romain3,Demurtas Davide4,Alibashe Ahmed Mohamed5,Piemonti Lorenzo6,Hirosue Sachiko1,Swartz Melody A.127,De Palma Michele8,Hubbell Jeffrey A.127,Baekkeskov Steinunn12

Affiliation:

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

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.

Funder

JDRF

École Polytechnique Fédérale de Lausanne

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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