Primary Human and Rat β-Cells Release the Intracellular Autoantigens GAD65, IA-2, and Proinsulin in Exosomes Together With Cytokine-Induced Enhancers of Immunity
| Autor: | Mohamed Alibashe Ahmed, Miriella Pasquier, Jeffrey A. Hubbell, Chiara Cianciaruso, Steinunn Baekkeskov, Edward A. Phelps, Romain Hamelin, Melody A. Swartz, Michele De Palma, Davide Demurtas, Lorenzo Piemonti, Sachiko Hirosue |
|---|---|
| Přispěvatelé: | Cianciaruso, C., Phelps, E. A., Pasquier, M., Hamelin, R., Demurtas, D., Ahmed, M. A., Piemonti, Lorenzo, Hirosue, S., Swartz, M. A., De Palma, M., Hubbell, J. A., Baekkeskov, S., Pathology/molecular and cellular medicine |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
endocrine system diseases Endocrinology Diabetes and Metabolism Fluorescent Antibody Technique Autoimmunity Exosomes Autoantigens Rats Sprague-Dawley 0302 clinical medicine Mice Inbred NOD Insulin-Secreting Cells Cells Cultured Proinsulin Membrane Glycoproteins Glutamate Decarboxylase Research Support Non-U.S. Gov't Endoplasmic Reticulum Stress Cell biology Intracellular endocrine system Antigen presentation 030209 endocrinology & metabolism Enzyme-Linked Immunosorbent Assay Biology Exosome Cell Line 03 medical and health sciences Islets of Langerhans Organ Culture Techniques Microscopy Electron Transmission Internal Medicine Journal Article HLA-DR4 Antigen Animals Humans Secretion Genetic Predisposition to Disease HSP70 Heat-Shock Proteins Receptor-Like Protein Tyrosine Phosphatases Class 8 Endoplasmic reticulum nutritional and metabolic diseases Dendritic Cells Microvesicles Rats 030104 developmental biology Diabetes Mellitus Type 1 Haplotypes Immunology Liposomes biology.protein Calreticulin |
| Zdroj: | Diabetes. 66(2) |
| ISSN: | 1939-327X |
| Popis: | The target autoantigens in several organ-specific autoimmune diseases, including type 1 diabetes (T1D), are intracellularmembrane 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 HLADR4. 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 chaperonesmay play a role in the initiation of autoimmune responses in T1D. © 2017 by the American Diabetes Association. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|