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 endoplas... More
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.
