Regular article
Immunopathology and infectious diseases
On the Etiology of Type 1 Diabetes: A New Animal Model Signifying a Decisive Role for Bacteria Eliciting an Adverse Innate Immunity Response

https://doi.org/10.1016/j.ajpath.2012.07.022Get rights and content
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The cause of type 1 diabetes (T1D) remains unknown; however, a decisive role for environmental factors is recognized. The increased incidence of T1D during the last decades, as well as regional differences, is paralleled by differences in the intestinal bacterial flora. A new animal model was established to test the hypothesis that bacteria entering the pancreatic ductal system could trigger β-cell destruction and to provide new insights to the immunopathology of the disease. Obtained findings were compared with those present in two patients dying at onset of T1D. Different bacterial species, present in the human duodenum, instilled into the ductal system of the pancreas in healthy rats rapidly induced cellular infiltration, consisting of mainly neutrophil polymorphonuclear cells and monocytes/macrophages, centered around the pancreatic ducts. Also, the islets of Langerhans attracted polymorphonuclear cells, possibly via release of IL-6, IL-8, and monocyte chemotactic protein 1. Small bleedings or large dilatations of the capillaries were frequently found within the islets, and several β-cells had severe hydropic degeneration (ie, swollen cytoplasm) but with preserved nuclei. A novel rat model for the initial events in T1D is presented, revealing marked similarities with the morphologic findings obtained in patients dying at onset of T1D and signifying a decisive role for bacteria in eliciting an adverse innate immunity response. The present findings support the hypothesis that T1D is an organ-specific inflammatory disease.

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Supported by Swedish Medical Research Council grant 65X-12219-15-6, EU-FP7-Health 2010 PEVNET 261441, and, in part, by NIH grant 2U01AI065192-06 (O.K. and T.L.). Human pancreatic islets were obtained from The Nordic Network for Clinical Islet Transplantation, supported by the Swedish National Strategic Research Initiative EXODIAB (Excellence of Diabetes Research in Sweden), and the Juvenile Diabetes Research Foundation.