New insight into early events in type 1 diabetes: role for islet stem cell exosomes.

Type 1 diabetes (T1D) is an autoimmune disease in which an inappropriate self-directed immune response affects and destroys insulin-producing b-cells in pancreatic islets leading to dysregulated blood glucose levels. T1D may affect people of any age, its clinical presentation is highly variable, and its incidence is increasing worldwide (1). The initial triggering events of T1D are unknown and their elucidation is of pivotal importance. Several factors might lead to the breakdown of b-cell– specific T-cell tolerance, including genetics, exogenous infectious pathogen, noninfectious environment agents, endogenous superantigens, or physiological stress events (2). The hallmark of autoimmune diabetes is insulitis, which progresses to a destruction of b-cells that results in clinical T1D. An altered balance between proinflammatory T-helper type 1 (Th1)/Th17 cells (g-interferon [IFN-g], interleukin [IL]-17) and Th2 immune response (IL-4, IL10) leads to T1D (3,4). Evidence also suggests that both genetic and environmental factors may induce local inflammatory response, where activated intraislet dendritic cells (DCs) prevent peripheral T-cell tolerance (5). Moreover, it has been recently demonstrated that the development of destructive insulitis is partly due to impaired islet-resident Foxp3 regulatory T cells (6,7). Several animal experimental models have been used for the investigation of the pathogenesis of T1D and it appears that a NOD mouse is the model of choice. NOD mice spontaneously develop early peri-insulitis and later intraislet insulitis caused by autoreactive T cells, but the reasons for the loss of tolerance to islets antigens are largely unknown. Prior to islets infiltration by autoreactive lymphocytes in the NOD strain, the abnormalities such as vascular pathology, increased b-cell endoplasmic reticulum stress, and upregulation of inflammatory cytokines may exist, which may result in b-cell death and release of the islet antigens (8). In this issue, Rahman et al. (9) use this experimental model to report that exosomes (EXOs) released from fibroblast-like, fast-replicating cells that express mesenchymal stem cell (MSC) markers in the islet may act as a trigger of the autoimmune response. It has already been established that both EXOs and MSCs may play a role in modulating autoimmunity, including T1D (10). Namely, insulinoma-released EXOs can stimulate the autoimmune responses in NOD mice by their ability to induce proinflammatory cytokines, including IL-6 and tumor necrosis factor-a, the effect that was Toll-like receptor–mediated as MyD88 was required for this adjuvant effect. Of importance, the candidate islet antigen, GAD65 kDa, was demonstrated to be expressed in these EXOs (11). However, a study by Rahman et al. (9) provides the first evidence that primary islets contain MSCs able to activate primed B and T autoreactive cells. The underlying mechanism of activation of autoreactive lymphocytes appears to be the release of EXOs, which promote expansion of diabetogenic T cells and accelerate the effect of T-cell–mediated destruction of the islets. It has been debated that the use of stem cells (SCs) holds a promise for the treatment of T1D due to their documented immunological and regenerative effects (12). SCs are undifferentiated cells capable of giving rise to virtually any tissue cells and have been categorized as embryonic SCs, cord blood SCs, and adult SCs. Adult SCs are undifferentiated multipotent cells present in all tissues. Bone marrow–derived MSCs are the most frequently used cells in investigation of T1D and have been reported to induce immunological tolerance toward b-cells through inhibition of autoaggressive T cells (13,14). Immunomodulatory function of MSCs was shown in