title: Exosomes released by islet-derived mesenchymal stem cells trigger autoimmune responses in NOD mice.
abstract: Exosomes (EXOs) are secreted, nano-sized membrane vesicles that contain potent immunostimulatory materials. We have recently demonstrated that insulinoma-released EXOs can stimulate the autoimmune responses in nonobese diabetic (NOD) mice, a spontaneous disease model for type 1 diabetes. To investigate whether primary islet cells can produce EXOs, we isolated cells from the islet of Langerhans of NOD mice and cultured them in vitro. Interestingly, cultured islets release fibroblast-like, fast-replicating cells that express mesenchymal stem cell (MSC) markers, including CD105 and stem-cell antigen-1. These islet MSC-like cells release highly immunostimulatory EXOs that could activate autoreactive B and T cells endogenously primed in NOD mice. Serum EXO levels and EXO-induced interferon-γ production were positively correlated with disease progression at the early prediabetic stage. Consistent with these observations, immunohistological analysis of pancreata showed that CD105(+) cells are restricted to the peri-islet area in normal islets but penetrate into the β-cell area as lymphocyte infiltration occurs. Immunization with EXOs promoted expansion of transferred diabetogenic T cells and accelerated the effector T cell-mediated destruction of islets. Thus, EXOs could be the autoantigen carrier with potent adjuvant activities and may function as the autoimmune trigger in NOD mice.
authors.affiliation: Division of Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA.
authors.forename: Muhammad Jubayer
authors.initials: MJ
authors.lastname: Rahman
authors.forename: Danielle
authors.initials: D
authors.lastname: Regn
authors.forename: Roman
authors.initials: R
authors.lastname: Bashratyan
authors.forename: Yang D
authors.initials: YD
authors.lastname: Dai
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002478:Cells, Cultured; D000071063:Endoglin; D055354:Exosomes / Q000276:immunology*; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D007515:Islets of Langerhans / Q000166:cytology*; D008214:Lymphocytes / Q000276:immunology; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007371:Interferon-gamma