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Primary Human and Rat β-Cells Release the Intracellular Autoantigens GAD65, IA-2, and Proinsulin in Exosomes Together With Cytokine-Induced Enhancers of Immunity.
- Source :
- Diabetes; Feb2017, Vol. 66 Issue 2, p460-473, 14p, 1 Diagram, 6 Graphs
- Publication Year :
- 2017
-
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. [ABSTRACT FROM AUTHOR]
- Subjects :
- B cells
LABORATORY rats
AUTOANTIGENS
PROINSULIN
EXOSOMES
CYTOKINES
GENE enhancers
IMMUNITY
ANIMAL experimentation
ANTIGENS
CALCIUM-binding proteins
CELL culture
CELL lines
DENDRITIC cells
DISEASE susceptibility
ELECTRON microscopy
ENZYME-linked immunosorbent assay
ENZYMES
FLUORESCENT antibody technique
TYPE 1 diabetes
ISLANDS of Langerhans
RESEARCH methodology
ARTIFICIAL membranes
MICE
PHOSPHATASES
PROTEINS
RATS
TISSUE culture
HLA-B27 antigen
MEMBRANE glycoproteins
HAPLOTYPES
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 66
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 120841472
- Full Text :
- https://doi.org/10.2337/db16-0671