Exosome-like microparticles can stimulate both innate and adaptive autoimmunity in non-obese diabetes mice (44.20)

Exosomes (EXO) are secreted intracellular microparticles that can trigger inflammation and induce antigen-specific immune responses. To test possible roles of EXO in autoimmunity, we isolated EXO from mouse insulinoma and examined their activities to stimulate the autoimmune responses in NOD mice, a model for human type 1 diabetes. We demonstrate that the EXO contains strong innate stimuli and expresses candidate diabetes autoantigens; it can activate splenocytes or purified APC through MyD88-dependent pathways, and result in T cell proliferation. To address whether exosomal antigens could be targets of the islet-specific autoimmunity, we monitored the spontaneously developed memory response in NOD mice for its reactivity to the EXO and compared the response with resistant strains. We found that older NOD females, which have advanced islet destruction, accumulated more EXO-reactive, IFN-gamma-producing lymphocytes than younger females or age-matched males, and that pancreatic lymph nodes of NOD but not resistant strains were enriched with EXO-reactive Th1 cells. Importantly, high titer of EXO-binding antibodies was also detected in serum of the NOD females but absent in resistant strains. Thus, certain exosomal antigens can be recognized by the autoreactive T cells and autoantibodies that are spontaneously developed in prediabetic NOD mice, supporting that EXO might be a possible autoimmune target in this diabetes-susceptible strain.